Peptidiomimetics in antifungal drug design.pdf

Anti-Infective Agents in Medicinal Chemistry, 2009, 8, 327-344 327

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Peptidomimetics and their Applications in Antifungal Drug Design

Shoeib Moradi, Saeed Soltani, Alireza M. Ansari and Soroush Sardari*

Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur

Institute of Iran, #69 Pasteur Ave., Tehran, Iran 13164

Abstract: The antimicrobial peptides represent diverse structures for drug design. They have been looked at as potential

sources of new antimicrobial drugs to combat the increasing threat posed by multiple drug resistant microorganisms. Un-

fortunately, peptides themselves provide inferior drug candidates because of their low oral bioavailability, potential im-

munogenicity, poor in vivo metabolic stability, high molecular weight and most importantly being exposed by enzymes

like proteases. Recent efforts to resolve disadvantageous peptide characteristics, and thus generating practical pharmaceu-

tical therapies, have focused on the creation of non-natural peptide mimetics. Peptidomimetic molecules may have re-

duced immunogenicity and improved bioavailability relative to peptide analogues. Also the artificial backbone makes

most peptidomimetics resistant to degradative enzymes thus increasing the stability of peptidomimetic drugs in the body.

In this article, after introducing antifungal peptides, benefits and limitations, and peptidomemetics usage are discussed and

applications in drug discovery process and antifungal research will be presented.

INTRODUCTION

The occurrence of fungal infections that have been seen in the growing populations of immunocompromised hosts, such as individuals infected with HIV, transplant recipients and patients with cancer, has increased dramatically in the last few decades [1]. Of the thousands of recognized fungal species, practically a couple, are pathogenic and produce mycotic infections in humans and animals. In tropical and subtropical developing countries, dermatophytes and Can-dida sp. can cause infections in humans and other animals, especially in immunocompromised patients. In addition, the number of reported cases of immunocompromised patients which often develop opportunistic and superficial mycoses, such as candidiasis, cryptococcosis and aspergillosis, has increased dramatically in recent years, especially in those with AIDS [2] The yeast fungus, Cryptococcus neoformans, has been identified as the fourth most common cause of life-threatening infection in AIDS patients. Potentially fatal in-fections with Candida albicans and other species of Candida are also known [3]. According to Sardari and Dezfulian, the fungi have varied susceptibility to different antifungal agents [4]. In other words, the dearth of wide-spectrum antifungal agents is of great alarm to medical mycologists and practi-tioners. Long-term treatment with the commonly used anti-fungals such as amphotericin B has toxic effects on the pa-tient; flucytosine and echinocandins have a restricted spec-trum, while azoles may result in strain resistance [5]. There-fore, in the search for a substitute form of treatment for fun-gal infections, the last decade has seen a rise in novel ap-proaches, such as therapeutic antibodies and peptide mole-cules. Antimicrobial peptides have newly become the focus of considerable interest as a candidate for a new type of anti-biotic, primarily due to their potency against pathogenic mi-

*Address correspondence to this author at the Drug Design and Bioinfor-

matics Unit, Department of Biotechnology, Pasteur Institute of Iran, #69 Pasteur Ave., Tehran, Iran 13164; Tel: (98-21) 6640-5535; Fax: (98-21)

6646-5132; E-mail: [email protected];[email protected]

crobes that are resistant to conventional antibiotics, as well as their broad-spectrum activity [6]. Since the first identifica-tion of cecropin [7] and defensin [8] in insect hemolymph and human neutrophils, respectively, several antimicrobial peptides have been isolated from a wide variety of organ-isms, including vertebrates, invertebrates, and plants [9]. Other than pathogen-lytic activities, these peptides have other properties like anti-tumor, mutagen activity, or act as signaling molecules [10]. In addition, they have a number of biotechnological applications, e.g. in transgenic plants [11], in aquaculture, and as aerosol spray for patients of cystic fibrosis [12]. Among AMPs, there is a group with consider-able fungicidal effect referred to as antifungal peptides (AFPs). Antifungal and antimicrobial peptides are becoming the focus of interesting molecules among scientists, as they are vital components of the innate defense of all species, they kill very quickly, do not simply select resistant mutants and are synergistic with potentially toxic conventional therapeu-tic agents against microbes. Some of these agents have reached clinical trials, while others are undergoing detailed preclinical testing [13]. Therefore, the search continues for new antibiotics that are active in vivo, fast acting and broad-spectrum, do not induce fungal and bacterial resistance and have limited side effects. In addition to the properties de-scribed above, they have low MICs and broad-spectrum ac-tivity in both low and high ionic strength conditions [14], neutralize lipopolysacharides [15], encourage injury healing [16] and have synergistic activity with conventional antibiot-ics [17]. Very few side effects have been reported. Synthetic congeners of natural antimicrobial peptides are good candi-dates. Synthetic congeners including a different series of peptides truncated successively from the carboxyl-terminal end of larger monomer and some analogs, which have lysine residues in place of two internal histidines or have a lysine added to the amino terminus of the original molecule. Not only synthetic congeners benefit from natural properties of antifungal peptides, but also with alteration in structural

328 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 4 Moradi et al.

characteristic of original antifungal peptides, their bioactivity would increase.

ANTIFUNGAL PEPTIDES

Classification of Antifungal Peptides

There is a great diversity of anti-fungal peptides, with large variations in molecular mass, N-terminal sequence and antifungal specificity. Antifungal peptides are classified in several ways. Two major classification of antifungal peptide included classification by their mode of action and by the source. They will be described briefly here.

According to the classification by the mode of action, AFPs are divided to the two groups. The first group acts by lysis, which occurs by means of several mechanisms. Lytic peptides can be amphipathic, that is, molecules with two faces, with one being positively charged and the other being neutral and hydrophobic. Some amphipathic peptides bind merely to the membrane surface and can disrupt the mem-brane structure without traversing the membrane. Others traverse membranes and interact distinctively with certain molecules. Lastly, other amphipathic peptides aggregate in a discriminating manner, forming aqueous pores of variable sizes, allowing passage of ions or other solutes [18]. The second peptide group interferes with cell wall synthesis or the biosynthesis of critical cellular components such as glu-can or chitin [19]. An excellent review of lipopeptide anti-fungal agents affecting cell wall synthesis has been pub-lished previously [20]. Also Antifungal peptide can be classi-fied according to their origin of isolation. Table 1 shows some antifungal peptide from different origin.

Mode of Action of Antifungal Peptides

The method of fungal cell lysis by peptides usually in-clude non-specific interaction with the membrane phosphol-ipids rather than binding to exact receptors on the cell mem-brane so that microorganisms develop resistance to antimi-crobial peptides at rates that are orders of magnitude less than those observed for conventional antibiotics [21]. On the down side, the toxicities of many of the peptides and their fast rate of clearance from the circulation mean that topical or in vitro applications may be more appropriate than sys-temic administration [22]. Antifungal peptides are found in numerous organisms, ranging from fungi through mammals [23]. The majority of antifungal peptides constitute a simple structural motif; they are most commonly short (<40 resi-dues) linear, cationic, amphipathic -helices. They exert an-tibacterial activity by cell membrane permeabilization and lysis, even though the accurate lytic mechanism has not been conclusively determined. Selectivity for the fungal cell ap-pears to be mediated by favorable electrostatic interaction between positively charged peptides and the negatively charged cell surface [24]. However, an excessively hydro-phobic peptide can bind arbitrarily to any cell membrane [25]. Antifungal peptide selectivity is dependent upon a pre-cise balance of peptide hydrophobicity and electrostatic charge. In general, studies propose that the overall physico-chemical parameters of antifungal peptides, rather than any specific receptor–ligand interactions, are responsible for anti-fungal activity [26]. As a result, antifungal peptides are at-tractive targets for biomimicry and peptidomimetic lead de-

velopment, as reproduction of critical peptide biophysical characteristics in an unnatural, sequence-specific mimicking the source oligomer should presumably be enough to donate antifungal efficacy, while circumventing the restrictions re-lated to peptide pharmaceuticals [27].

Models of Peptide Interaction with Lipid Membranes

According to the above-mentioned mode of action, a pep-tide which has lethality effect on fungi should be capable of forming ion channels in membrane by aggregation (pseu-doionophores) and insertion in order to span cell membrane with 2.5-4.0 nm thickness (depending upon lipid composi-tion) and should have at least 12 amino acids [28, 29]. Being laterally amphipathic meaning that one face of the helix dis-playing hydrophobic residues, while the opposite face dis-plays hydrophilic residues, the peptide can form hydrophilic ion channels or pores and at the same time remain in contact with the hydrophobic components, e.g. fatty acyl moieties [30]. Based on these properties, two principal modes of ac-tion for membrane-perturbing peptides have been proposed: pore formation across the lipid bilayer or a "carpet" mecha-nism, lysing the membrane in a detergent-like manner. In the latter model, peptides "carpet" the surface of a target mem-brane and when sufficiently accumulated, create numerous pores [30]. The transmembrane model involves the peptides forming pores through the outer membrane: the "barrel-stave" [31] and toroidal pore [32] mechanisms. In these models, the peptides oligomerize to form pores through the membrane. The pores act as non-selective channels for ions, toxins and metabolites, thus preventing the organism from maintaining homeostasis. Peptides with 20 or more amino acids lend themselves to these mechanisms, as they are able to span the lipid bilayer when in -helical conformation. A key difference between these two mechanisms is the posi-tioning of the headgroup region of the lipid molecules with respect to the peptide. In the barrel-stave mechanism, the headgroups remain located along the membrane surface, while the pore is formed by the interaction of the peptide within the hydrophobic core of the membrane. The trans-membrane pore is lined by the hydrophilic surface of the peptide. According to BSPM (Barrel-Stave Pore Model), AFPs should have distinct structure such as -helix or -sheet or both and have hydrophobic interaction with the tar-get membrane. By contrast, toroidal pores are formed when the peptides insert in such a way to cause the inner and outer membrane leaflets to curve and the lumen is lined by the hydrophilic surface of the peptide interspersed by the phos-pholipid headgroups. TPM (Toroidal Pore Model) is based on formation of several short-lived clusters of an undefined nature of secondary structure [75]. Preference for barrel-stave vs. toroidal pore may depend on several factors includ-ing the peptide length and membrane thinning effect induced by the peptide [76].

Disadvantages of Antifungal Peptides

The development of peptides as drugs is problematic as a result of poor oral and tissue absorption, rapid proteolytic cleavage and poor shelf-life or stability. Most proteins and small peptides are easily proteolyzed, rapidly excreted and poorly bioavailable. Much effort has been expended to find ways to replace portions of peptides with nonpeptide struc-

Peptidomimetics and their Applications in Antifungal Drug Design Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 4 329

Table 1. Antifungal Peptides from Different Origins

Peptide Source Length Mode of Action Target fungus MIC ( g/ml) Refs.

Mammalian antifungal peptides

Histatin 3 Saliva of humans 31 Lysis C. albicans 75 [33]

Halocidin Halocynthia aurantium 18 Lysis C. albicans 10 [34]

Protegrins 1 Human, porcine 16 Lysis C. albicans 3 [35]

Tritrptcin Human, porcine 13 Lysis A. flavus 250 [36]

PAMP Human, porcine 24 Unknown C. albicans 23 [37]

NP-3B Rabbit 33 Lysis A. fumigates 100 [38]

SAMP29 Sheep 45 Lysis C. albicans 4 [39]

Insect and amphibian antimicrobial peptides

Melitin Apis mellifera 25 Lysis C. albicans 1.5 [40]

Cecropins B H. cecropia 35 Lysis A. fumigatus 9.5 [41]

DSP Leaf beetle 41 Unknown C. albicans 7 [42]

Magainin 2 Xenopus laevis 23 Lysis C. albicans 80 [43]

Drosomycin D. melanogaster 44 Lysis F. oxysporum 5 [44]

Tenecin Inset defencin 43 Lysis C. albicans 100 [45,46]

Cicadin Juvenile cicadas 45 Lysis C. albicans 70 [47]

Esculentin-1 Phyllomedusa sauvagii 47 Lysis C. albicans 11 [48]

Brevin -2 Phyllomedusa sauvagii 40 Lysis C. albicans 10 [49]

Bacterial and fungal antifungal peptides

Anafp Aspergillus niger 55 Lysis C. albicans 50 [50]

Fungicin M-4 Bacillus licheniformis Cyclic peptide Unknown Mucor sp. 8.0 [51]

HP Helicobacter pylori 11 Unknown C. albicans 12.5 [52]

Helioferin A Mycogone rosea Lipopeptide Unknown C. albicans 5.0 [53]

Iturin A Bacillus subtilis Lipopeptide Lysis S. cerevisiae 22. [54]

Leucinostatin A Phaeohelotium lilacinum Amino-lipopeptide Unknown C. neoformans 0.5 [55]

Nikkomycin X Streptomyces tendae Peptide-nucleoside Chitin synthesis C. immitis 0.125 [56]

Polyoxin D Streptomyces cacaoi Trinucleoside peptide Chitin synthesis C. immitis 0.125 [57]

Schizotrin A Schizotrix sp. Cyclic undecapeptide Unknown C. albicans 0.02 [58]

Trichopolyn A Trichoderma polysporum Amino-lipopeptide Lysis C. neoformans 0.78 [59]

Pneumocandin

A0

Zalerion arboricola Lipopeptide Glucan synthesis C. albicans 0.1 [60]

FR900403 Kernia sp. Lipopeptide Chitin synthesis F. oxysporum 0.4 [61]

CB-1 Bacillus licheniformis Lipopeptide Chitin binding F. oxysporum 50 [62]

Plant antifungal peptides

Zeamatin Zea mays 27 Lysis C. albicans 0.5 [63]


(Table 1) contd….

Peptide Source Length Mode of Action Target fungus MIC ( g/ml) Refs.

ACE-AMP1 Allium cepa 84 Unknown F. oxysporum 0.3 [64]

Pe-AFP1 Passiflora edulis 25 Lysis A. fumigatus 32 [46]

Pinin Red Bean 45 Unknown F. oxysporum 3.5 [65]

Coccinin Runner beans 10 Unknown F. oxysporum 7.5 [66]

Cicerarin Green chickpea 20 Unknown F. oxysporum 8.2 [67]

Gymnin Yunnan bean 10 Unknown F. oxysporum 59 [68]

Beta-basrubrin Ceylon spinach seeds 36 Unknown F. oxysporum 12.5 [69]

Synthetic and semisynthetic antifungal peptides

LY303366 Lipopeptide 6 cyclic Glucan synthesis Candida krusei 0.5 [70]

D4E1 Linear peptide 17 Lysis A. flavus 26 [71]

MP1 Linear peptide 11 Unknown C. albicans 5 [72]

Dhvar Linear peptide 14 Unknown C. albicans 14 [73]

Cilofungin Lipopeptide Lipopeptide Glucan synthesis C. albicans 0.62 [74]

tures, called peptidomimetics, in the hope of obtaining more bioavailable entities [30]. Peptidomimetics can be seen as probes used in the transition pathway of small molecule drug design. Cyclization of the peptide backbone and its modifica-tion with aromatic residues constitutes an effective approach to mimic drug structures in the design process and circum-vents obstacles associated with delivery and formulation of peptides. In the recent years [25] examples of mimicking p-turn structures has led to combining design strategies with molecular libraries, demonstrating that peptidomimetics can provide valuable clues about receptor similarities not re-vealed by their endogenous ligands.

PEPTIDOMIMETICS

Recent efforts to reorganize disadvantageous peptide characteristics, and thus generate viable pharmaceutical therapies, have focused on the creation of non-natural pep-tide mimics. A peptidomimetic is a small protein-like chain designed to mimic a peptide which is often used in the litera-ture to indicate a multitude of structural types that differ in fundamental ways. The term of peptidomimetic is often ap-plied to highly modified analogs of peptides without distin-guishing how these differ from classical analogs of peptides. These Non-natural, sequence-specific peptidomimetic oli-gomers are being designed to mimic bioactive peptides, with potential therapeutic application. These peptidomimetics can be based on any oligomer that mimics peptide primary struc-ture through use of amide bond isosteres and/or modification of the native peptide backbone, including chain extension or heteroatom incorporation. Peptidomimetic oligomers are often protease-resistant, and may have reduced immuno-genicity and improved bioavailability relative to peptide ana-logues [77]. In addition to primary structural mimicry, a se-lect subset of the sequence-specific peptidomimetic oli-gomers, the so-called ‘foldamers’ [78], exhibits well-defined

secondary structural elements such as helices, turns and small, sheet-like structures [79]. When peptide bioactivity is contingent upon a precise 3D structure, the capacity of a biomimetic oligomer to fold can be very important. They typically arise from modification of an existing peptide in order to alter the molecule's properties. For example, they may arise from modifications to change the molecule's sta-bility or biological activity [80, 81]. This can have a role in the development of drug-like compounds from existing pep-tides. These modifications involve changes to the peptide that will not occur naturally (such as altered backbones and the incorporation of non-natural amino acids). Pepti-domimetics are part of the wide effort by researchers, re-search labs and institutions to create cures for cancer by means of restoring or activating apoptotic pathways in spe-cific cells. An example of peptidomimetics were those de-signed and synthesized with the purpose of binding to target proteins in order to induce cancer cells into a form of pro-grammed cell death called apoptosis [82]. Basically, these work by mimicking key interactions that activate apoptotic pathway in the cell. The unfavorable pharmacokinetic prop-erties associated with peptides when used as orally adminis-tered drugs can, in principle, be avoided by development of peptidomimetics. The general strategy when preparing pepti-domimetics is to replace segments related to undesired prop-erties with non-peptidic structures, while attempting to main-tain the ability to elicit the same or improved biological re-sponse as the native peptide [83, 84].

Classification of Peptidomimetics

Based on Rikpa and Rich classification [85], three most important classes of peptidomimetics have been described. The first type includes structures that mimic the local topog-raphy about an amide bond, i.e., amide bond isosteres, pyr-rolinones or short portions of secondary structure ( turns).


The peptide backbone mimetics are also known as type-I mimetics. The first class is characterized by backbone changes, such as incorporation of amide bond isosteres and turn mimetics. The literature concerning peptidomimetics of class I including stabilized turn mimetics represented as bi-cycles [86, 87], aromatics [88, 89] and cyclic compounds [90]. These mimetics regularly match the peptide backbone atom-for-atom, while retaining functionality that makes sig-nificant contacts with binding sites. Latest studies paid atten-tion to transition-state isosteres or collected substrate/product mimetics designed to mimic reaction pathway intermediates of the enzyme-catalyzed reactions. The reduced amide isos-tere developed by Szelke et al. [91] and the statine (hy-droxylmethylene) isostere were early mimetics used to de-sign inhibitors of a variety of aspartic proteases [92], and their success led to other tetrahedral intermediate mimics such as the hydroxylethylene and hydroxyethylamine isos-teres. Cathepsin K, is new type-I peptidomimetic which is inhibitor of cysteine protease [86]. Two small-molecule in-hibitors with an IC50 of 0.3 μM and 0.013μM have been de-signed lately, by Maibaum and co-workers [93, 94] which are orally active inhibitors of renin, the protease that cata-lyzes the first reaction in the renin-angiotensin system. The cysteine protease interleukin-lP-converting enzyme (ICE) inhibitor was designed by Dolle et al. [95] to generate potent aldehyde inhibitors of ICE. McKittrick et al. [96] designed a novel triple inhibitor of endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) as a type-I peptidomimetic inhibitor. It has been shown that opportunistic fungi such as Candida albicans require N-myristoyltransferase (NMT) for viability. Brown et al. [97] created type-I mimetic compounds which are selective for C. albicans over human NMT.

The second class of peptidomimetic is referred to as ligands exerting the same biological response as the native peptide ligand without any obvious structural resemblance (functional mimetics). The second type of mimetics is type-II or the functional mimetics, which are small nonpeptide molecules that binds to a peptide receptor. Initially these were presumed to be direct structural analogs of the natural peptide, but characterization of both the endogenous peptide and antagonist binding sites by site-directed mutagenesis [98] indicated that antagonists bind to subsites that are dif-ferent from those used by the parent peptide for a large num-ber of receptors. As a result, these functional mimetics do not essentially mimic the structure of the parent compound or hormone.

The third class is represented by peptidomimetics with a nonpeptidic core structure, which position key functionalities for interactions with the receptor in a closely related way as the native peptide. Some examples from the vast literature [86] in the field are peptidomimetics of vasopressin [99], oxytocin [100], LHRH [101], somatostatin and angiotensin II [102, 103]. Type-III mimetics represent the idyllic pepti-domimetics in that they possess novel templates which, though appearing unrelated to the original peptides, contain the necessary groups positioned on a novel nonpeptide scaf-fold to serve as topographical mimetics [104, 105]. At pre-sent, there is no systematic way to transform the structure of an enzyme-bound peptide substrate analog into a nonpeptide ‘mimetic’.

Type III peptidomimetics resemble the peptides, but em-ploying a non-peptide scaffold to position key pharmacopho-res for receptor interaction, whereas type II mimetics, which are functional agonists or antagonists, do not structurally mimic the native peptide [106]. A wide variety of pepti-domimetic building blocks have been developed in the past: e.g. peptoids [107], sulphonamides [108], ureapepti-domimetics [109], hydrazinopeptidomimetics [110], -peptides [111], oligopyrrolinones [112], peptidosulfona-mides [113], oligocarba-mates [114], oligoureas [110], aza-tides [111], and ethoxyformacetais [115] with unnatural oli-goamide backbones which are self-organized at the molecu-lar level to form stable helices useful to mimic protein sec-ondary structure elements [116]. The predictability of fold-ing of these oligomeric strands led to the development of molecules with functions including potent inhibitors of pro-tein-protein interactions [117-119]. A set of novel type-III mimetics have been obtained and found to have activity to-wards Factor Xa with IC50=5 μM [120]. Sall et al. and Chir-gadze et al. [121, 122] designed Type-III peptidomimetic inhibitors of thrombin also. Another type-III mimetic was developed by a group that used pyranoses as templates to design thrombin inhibitors [98]. Some type-III mimetics of Inhibitors of Ras-farnesyltransferase (R-FT) have been de-veloped by mimicking the carboxy-terminal CAAX motif which is the signal for farnesylation of Ras proteins [123-125].

Such "unnatural biopolymers '' may have markedly dif-ferent physicochemical proper-ties than natural peptides, including a superior pharmacological profile for develop-ment into therapeutic agents [126]. Finding unnatural oli-goamide backbones can adopt well-defined and controlled helical secondary structures suggested that one could use them as scaffolds to distribute charged side chains in a pre-dictable manner for de novo design of cationic amphiphilic molecules mimicking natural host defense -peptides. An-timicrobials based on either -peptides 314, 2.512, or 2.710,12 helical folds [127-131] or on peptoids polyproline type I-like [132] have been found to exhibit selective (non-hemolytic) and potent antibacterial activity against both Gram-positive and Gram-negative bacteria and fungi. Most antimicrobial peptidomimetics are typically discrete non-natural oligomers whose units are in many cases, connected via amide bonds. Much of the synthetic interest in peptidomimetics comes from the fact that these oligomers can present a wide variety of side chains which could be chemically identical to those found in natural peptides, but along an artificial backbone. The consequence of this hybrid structure is that pepti-domimetics can mimic the conformation and functionality of biopolymers yet are not limited by the side chains of the main twenty naturally occurring -amino acid building blocks. Also the artificial backbone makes most pep-tidemimetics resistant to bio-degradation enzymes thus in-creasing the stability of peptidomimetic drugs in the body [133].

SPECIFICATIONS AND BIOACTIVITY OF PEPTI-DOMIMETICS

-Peptides

-peptides consist of amino acids, which have their amino group bound to the carbon rather than the carbon


as in the 20 standard biological amino acids. The only com-monly naturally occurring amino acid is -alanine. Al-though it is used as a component of larger bioactive mole-cules, -peptides in general do not appear in nature Fig. (1). Due to this reason, -peptide-based antibiotics are being ex-plored as ways of evading antibiotic resistance. In amino acids, both the carboxylic acid group and the amino group are bound to the same carbon, termed the carbon (C ) be-cause it is one atom away from the carboxylate group. In amino acids, the amino group is bound to the carbon (C ), which is found in most of the 20 standard amino acids. Only glycine lacks a carbon, which means that there is no -glycine molecule. The chemical synthesis of amino acids can be challenging, especially given the diversity of functional groups bound to the carbon and the necessity of maintaining chirality. In alanine molecule, the carbon is achiral, however, larger amino acids have a chiral C atom. The -peptides are by far the best well-studied pepti-domimetics. Because the backbones of -peptides are longer than those of peptides that consist of -amino acids, -peptides form different secondary structures. The alkyl substituent at both the and positions in a amino acid favor a gauche conformation about the bond between the -carbon and -carbon. This also affects the thermodynamic stability of the structure. -peptides are stable against proteolytic degradation in vitro and in vivo, an important advantage age over natural peptides in the preparation of peptide-based drugs [8]. -peptides have been used to mimic natural peptide-based antibiotics such as magainins, which are extremely powerful but difficult to use as drugs because they are degraded by proteolytic enzymes in the body [9].

L- -alanine -alanin

Fig. (1). Structure of alpha and beta alanine.

Two main types of -peptides exist: as it shown in Fig. (2), those with the organic residue (R) next to the amine are called

3-peptides and those with position next to the car-

bonyl group are called 2-peptides [5].

(3) ...

NH

O

NH

RR

O

NH

R

O

NH

R

O

...

(1) ...

NHNH

O

NH

O

O

NH...

O

(2) ...NH

R O

NH

R O

NH

R O

NH

R O

...

Fig. (2). 1) -peptide, 2) 3-peptide, and 3)

2-peptide general struc-

tures.

Many types of helix structures consisting of -peptides have been reported [6]. These conformation types are distin-guished by the number of atoms in the hydrogen-bound ring that is formed in solution; 8-helix, 10-helix, 12-helix, 14-helix, and 10/12-helix. -peptides have more conformational freedom than -peptides, because of an additional methylene unit present in the polymer backbone. Consequently, whereas -peptide helices most commonly adopt the -helix conformation, -peptide sequences have been shown to adopt several distinct helical conformations, the choice of which depends largely upon the substitution pattern at back-bone C and C atoms [134-136]. Of these, the -peptide 12-helix and the 14-helix have been successfully employed as magainin mimics. The terms ‘12-helix’ and ‘14-helix’ corre-spond to the number of atoms participating in a ring created by intrachain hydrogen bonds. Recent studies in which -peptides were designed to mimic the magainin have helped to illustrate which physical characteristics are critical for ideal antibacterial efficacy and biocompatibility in non-natural oligomers. DeGrado and co-workers [137] first re-ported the de novo design of amphipathic, cationic, mono-substituted -peptide 14-helices as antibacterial compounds against the Gram-negative bacterium K91 Escherichia coli. Their study led to design of non-hemolytic analogues such as 1 in Fig. (3) [133]. Although potent antibiotics, these -peptides displayed poor selectivity for bacteria, as indicated by extensive mammalian red blood cell lysis (haemolysis). Assuming that excessive side-chain hydrophobicity was re-sponsible for the poor selectivity observed, Liu and col-leagues [138] modified their original 14-helix designs to substitute a valine-like ( -HVal) residue with a less hydro-phobic alanine-like ( -HAla) residue. In support of their original hypothesis, this modification abolished haemolytic activity, while retaining good antibacterial efficacy in both 12- and 15-residue oligomers.

Generally, compounds that are not hemolytic at relative concentrations of their antimicrobial activity are typically deemed ‘‘selective’’ and have the potential for promising therapeutics that may kill microbial but not mammalian cells. In addition, hemolysis, by far the most common measure of mammalian toxicity, may not be the best predictor [139].

Simultaneously and independently, Seebach and Mathews [140] studied quite similar mono-substituted -peptides, also designed to adopt the -peptide 14-helix for antimicrobial and hemolytic activity and demonstrated that "

2/

3" type peptides such as 2 in Fig. (3) can display selec-

tivity [137, 140]. Interestingly, although haemolytic activity was comparable, this sequence difference alone resulted in a one order of magnitude reduction in antibacterial activity relative to DeGrado’s refined oligomers. In 2000, Gellman and coworkers has reported a 17-residue -peptide 12-helix, which they called ‘ -17’, such as 3 in Fig. (3) that formed helices just like the class of host-defense peptides known as the magainins, which have 20–30 residues [127]. This par-ticular -17 was reported to be effective against two patho-gens that are resistant to common antibiotics plus they are not hemolytic. Unlike DeGrado’s monosubstituted 14-helices, -17 is disubstituted at C and C to form intraresi-due five-membered rings and consequently possesses sig-nificantly less conformational freedom than either De-Grado’s or Seebach’s oligomers. Therefore, conformational

C

CH2

O-

O

N+

H

H

H

H

H

C

N+

C

CH3

H

O-

O

H

HH


rigidity does not appear to adversely affect activity or selec-tivity. In fact, Gellman’s group has recently described a -peptide 12-helix with both mono- and di-substituted resi-dues, with activity comparable to -17 and magainin [141]. Regardless of the particular oligomer identity, it is clear that the repertoire of peptidomimetic antibiotics will soon expand beyond the exclusive realm of -peptides.

Peptoids

Peptoids, or N-substituted glycines, with -chiral side chains are of particular interest for their ability to adopt sta-ble, helical secondary structure in organic and aqueous solu-tion [142]. These molecules are specific subclass of pepti-domimetics. They are closely related to their natural peptide counterparts, but differ chemically in that their side chains are appended to nitrogen atoms along the molecule's back-bone, rather than to the -carbons, as they are in amino acids (Fig. 4). Such family of molecules is essentially invulnerable to protease degradation [143] and therefore is biostable and less prone to immune system recognition [144]. Despite the achirality of the N-substituted glycine backbone and its ab-sence of hydrogen bond donors, oligopeptoids are able to adopt stable, chiral helices when substituted with -chiral, sterically large side chains (Fig. 5). [145, 146]. Several dif-ferent families of biological oligomers have been synthesized [147, 148] and proposed as novel mimics of natural mole-cules such as magainin, a helical, amphipathic antimicrobial peptide (Fig. 6). [127, 145, 149] Their ability to form stable helices makes peptoids an excellent candidate for mimicry of bioactive molecules that rely on helical structure for proper function. In addition, peptoid oligomers have been shown to be protease resistant and are easily and inexpensively pro-

duced by solid-phase synthesis [144, 150], traits that are critical for the successful development of a peptidomimetic therapeutic agent. In order to probe for peptoid, selective peptidomimetics of magainin-II was designed by Barron and Patch, which signified the first bioactive folded peptoid (Fig. 7) [132].

HN

NH2

OR

n

Fig. (4). N-Substituted glycine oligomers or polypeptoid.

Another study was done by Statz et al. due to synthesize peptoid like 6, which specifically designed for robust, water-resistant anchorage to biomaterial surfaces and long-term resistance to fouling in the biological environment. The pep-tidomimetic polymer was synthesized by synthesis of a 20-mer N-methoxyethyl glycine peptoid (Fig. 8) [151].

N, N -Linked Oligoureas

N, N -linked oligoureas with proteinogenic side chains are peptide backbone mimetics that belong to the -peptide lineage. They are formally obtained by simple substitution of NH for the CH2 of the amino acid constituents of 4-peptides. By using combination of NMR spectroscopy and circular dichroism it has been shown that oligoureas, as short as seven residues can adopt a stable right- handed 2.5-helical secondary structure stabilized by 12- and 14-membered H-bonded rings in various solvents such as pyridine, methanol,

Fig. (3). 1: Selective antimicrobial -peptides. 2: 2/

3 peptide. 3: " -17" -peptide.

HNH NH NH

O O

NH2

O

NH2

4 or 5

1

CH3

NH NH NH NH NH NH NH2

O O O O O O ONH

2

+NH

2

+

2 33

NH2

O

NH NH

O O

NH NH

O O

NH2

NH

O

NH

O

OH

22


and trifluoromethanol [152-154] reminiscent of the helix described for the corresponding 4-peptides.

Fig. (5). Large peptoid oligomers.

NH

NN

NN

NN

NN

O

O

O

CH3

CH3

O

O

CH3

CH3

O

NH2

O

NH

NH

NH2

O

H

CH3

NH2

OH

14

Fig. (6). The chemical structure of a peptoid 22-mer surfactant

protein C, a small protein that plays an important role in surfactant

replacement therapy for the treatment of neonatal respiratory

distress syndrome.

NH2

ON

N

O

H

H

O

N

NH 3

H

+5

Fig. (7). Helical peptoid mimics of magainin-II amide.

NH

NH

O

O

Anchoring peptide

O

-

20-

Fig. (8). Biomimetic antifouling N-substituted glycine polymer

(peptoid) containing a C-terminal peptide anchor derived from resi-

dues found in mussel adhesive proteins for robust attachment of the

polymer onto surfaces.

This strong helix folding propensity, together with the diversity of available side chain appendages and the ex-pected resistance to protease degradation, make the oligourea backbone a promising candidate for biomedical applications. It has been shown recently that -amino acid residues bear-ing side chains branched at the first carbon have a strong 314 helix propensity [155,156]. The helix stability can be signifi-cantly enhanced by acylating the free amino terminus of oligoureas [157]. Although the amide bond is undoubtedly a consensual motif for the elaboration of peptidomimetics folding oligomers ("foldamers"), it was shown that the urea moiety, by its capacity to form auto-complementarities and bidirectional hydrogen bonds can be substituted for the am-ide linkage to generate oligomeric strands with strong pro-pensity for helix formation [158,159].

DESIGN AND MODELING OF PEPTIDOMIMETICS

Recently significant progress has been made in use of Computer-Aided Molecular Design (CAMD) of novel mole-cules with desired properties, these methods typically rely on two stages: the first stage is forward modeling [160], through which Quantitative Structure Activity Relationship (QSAR) process is accomplished by application of non-linear model-ing procedures such as Artificial Neural Networks (ANN). As example of this strategy, Soltani et al analyzed over 100 antifungal peptides by artificial neural networks and ob-served that most important physicochemical parameter af-fected on bioactivity of antifungal peptides are Log P and relative amphipaticity [161].

The second stage is model inversion/optimization which is the use of optimization algorithms in exploitation of the first stage results in discovery of molecules with improved activity [159]. Several parameters affect the activity of anti-fungal peptides such as sequence, size, charge, degree of structure formation, cationicity, hydrophobicity and amphi-pathicity Use of ANN could help us evaluate the importance of these structural parameters in bioactivity of AFPs and eventually the most probable model of AFPs' mechanism of action. The antimicrobial peptides have little sequence ho-mology, despite common properties [13]. Thus it is difficult to develop methods for predicting the antimicrobial peptides based on similarity. Moreover, experimental methods for identification and design of antimicrobial peptides are costly, time consuming and resource intensive.

Nchm = N-(Cyclohexylmethyl)glycine

H

O

CH3

H3C

Nme = N-(methoxyethyl)glycine

Npm = N-(1-phenylmethyl)glycine

Nrpe = (R)-(N)-(1-phenylethyl)glycine

-20


Thus there is a need to develop computational tools for predicting antifungal peptides, which could be used to design potent peptides against fungal pathogens. Recently research-ers attempted to model antimicrobial peptide by QSAR and other in silico methods. For example a HMM (Hidden Markov Model) based method has been developed for searching conserved motifs of -defensin family in genome databases [157]. Combinatorial chemistry, high-throughput screening, and analogous techniques have become powerful tools to promote drug discovery in peptidomimetics research. Current pharmaceutical research has taken advantages of newer computational methods, the so-called computer-aided drug design, and other physiochemical techniques such as X-ray crystallography and NMR.

The main goal in rational mimetic design is to translate the structural information in the native peptide into low mo-lecular weight non-peptidic molecules. Over the past years, many 3D structures of biological targets have been solved and have been successfully used to design new, pharmaco-logically useful compounds. Different computer-aided de-sign methods, e.g. 3D pharmacophore model, 3D quantita-tive SAR (QSAR), docking and de novo design have been extensively used [162]. As an example for QSAR and SAR studies, we follow up this section by a SAR study of some peptidomimetics that play role of microbial inhibition, through their structures. This example significantly shows the relation between peptide structure of these substrates and their ability for inhibition.

Inhibit activity of cell wall biosynthesis enzymes are categorized under antimicrobial agent family. One of the most suitable targets for these inhibitors is Glucosamine-6-phosphate synthase (G6Ps), which is known as the first step enzyme of cell wall biosynthesis process. N3-(4-methoxy-fumaroyl)-L-2,3 diaminopropanoic acid (FMDP), N3-(fum-aramoyl)-L-2, 3-diaminopropanoic acid (FCDP) or N4-(4-methoxyfumaramoyl)-L-2,4diaminobutanoic acid (FMDB) are mentioned as an instance for peptidomimetic glutamine analogues, play the role of powerful inhibitor of G6Ps (Fig. 9).

Fig. (9). 1) FMDP general structure. "R" shows additional amino

acids. 2) FCDP general structure. 3) FMDB general structure.

Unfortunately, some of these substrates are not capable to penetrate or pass the cell wall and reach target enzymes, therefore, they may not act effectively against whole cells. Thus, observations have been focused on new solutions for this problem. Microorganisms have peptide transporters to

absorb the metabolites of proteins. A suggested idea in order to resolve the problem is incorporating native peptide, and producing peptidomimetics prodrugs.

Peptide transporters accumulate them actively and will be reactivated by intracellular peptidase action. Table 2 shows the structure–antibacterial activity relationship, which have been constructed for mentioned peptidomimetic prodrugs, using E. coli K-12 Morse 2034 (trp, leu) (CGSC 5071), which is a wild-type with respect to Opp, Dpp and Tpp traits. Opp, Dpp and Tpp are peptide transporters with well-characterized features that let them to be distinguished from each other, but they also share certain substrate recognition features, in fact, some peptides can be taken up by more than one transporter. On the other hand, Table 3 introduces struc-ture-penetration activity of peptidomimetc prodrugs as ligands of Dpp and Opp transporters. Dpp and Opp are typi-cal ATP consuming transporters; each comprises four mem-brane proteins with a periplasmic peptide binding protein DppA or OppA, respectively.

These values directly influence the total effectiveness of the mentioned antibacterial peptidomimetics because of the problem of penetration as it was described before.

QSAR bioactivity modeling of antimicrobial dodeca pep-tide of Bac2A indicated that good activity was not solely dependent on the composition of amino acids or the overall charge or hydrophobicity, but rather required particular lin-ear sequence patterns [163]. In a study, the construction of a mathematical model for prediction, prior to synthesis, of peptide antibacterial activity against Pseudomonas aerugi-nosa had been described [164]. By use of novel descriptors quantifying the contact energy between neighboring amino acids in addition to a set of inductive and conventional quan-titative structure-activity relationship descriptors, it is possi-ble to model the peptides antibacterial activity [164]. Fur-thermore, by use of smoothed amino acid sequence descrip-tors, the structural characteristics important for antimicrobial activity are determined [165]. Although there is no unified way of designing peptidomimetics, certain computer applica-tions might be of help in this regard. Recently SuperMimic software is introduced by Goede et al. [166] which is a tool for finding potential non-peptidic building blocks that can replace or mimic parts of a protein, or peptide and con-versely for identifying locations within a protein where such building blocks can be inserted. It identifies compounds that mimic parts of a protein, or positions in proteins that are suitable for inserting mimetics. Photo-switchable compounds are becoming increasingly popular for a series of biological applications based on the reversible photo-control of struc-ture and function of biomolecules. Villin is a 92.5 kDa tis-sue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin contains multiple gelsolin-like domains capped by a small (8.5 kDa) "head-piece" at the C-terminus consisting of a fast and independ-ently-folding three-helix bundle that is stabilized by hydrophobic interactions.

The headpiece domain is a commonly studied protein in molecular dynamics due to its small size and fast folding kinetics and short primary sequence. Recently, Fullbeck et al. [167] used Supermimic software in order to be able to induce folding of the 35-residue subdomain (H35) at its C-

O

O

NH

HN

OHO

O

NH

R

CH3

(2)O

O

NH

HN

OHO

O

NH

R

CH3

O

H3C

(3)

H3CO O

O

NH

HN

O OHO

NH

R

CH3

(1)


Table 2. Antibacterial Activities of Glutamine Analogue Peptidomimetics Against E. coli K-12 Morse 2034 (trp, leu). Activities are

expressed as the amounts in nmol producing inhibition zones of 25 mm, obtained by extrapolation from plots of inhibition zone

diameters versus amounts of peptidomimetics [173]. Nva stands for norvalyl (2-amino pentanoic acid); Sar stands for sarcosyl (N-

methyl glycyl)

Peptidomimetics M2034 Peptidomimetics M2034

Leu-FMDP 80 AcNva-FMDP >5000

Lys-FMDP 180 FMDP-Leu >1000

Met-FMDP 90 FMDP-Met >3500

Nva-FMDP 60 FMDP-FMDP >5000

Phe-FMDP 80 FCDP-Ala >5000

Tyr-FMDP 200 FCDP-Met >5000

Nva-FMDB 150 Nva-FMDP-Nva 230

FMDP-Ala 700 SarNva-FMDP 290

Gly-FMDP >3000 LysNva-FMDP 150

Table 3. Percentage of Binding Peptidomimetics to DppA and OppA. The percentage inhibition of binding to DppA and OppA were

determined using Gly [125I]Tyr, and [125I2]TyrGlyGly as ligands respectively. The molar ratio of peptidomimetic to ligand was

10:1 in all cases [173]

Peptidomimetics

inhibition of

binding to

DppA%

inhibition of bind-

ing to OppA% Peptidomimetics inhibition of bind-

ing to DppA%

inhibition of bind-

ing to OppA%

Gly-FMDP 0 - Val-FMDP 75 -

SarNva-FMDP - 83 AcNva-FMDP 0 -

Leu-FMDP 80 - Nva-FMDB 93 -

Met-FMDP 88 - FMDP-Ala 14 -

Nva-FMDP 99 - FMDP-Leu 36 -

Phe-FMDP 94 - FMDP-Met 5 -

Tyr-FMDP 73 - Lys-FMDP - 24

LysNva-FMDP - 89 FMDP-FMDP 0 -

Nva-FMDP-Nva - 91 FCDP-Ala 49 -

terminus of the villin headpiece by irradiation, to replace parts of its main-chain by a photoswitch without changing the overall structure of the sub-domain.

OTHER APPLICATIONS

Peptidomimetics are not only applied in the field of anti-fungal peptides design but also has applications in other re-search area in order to design new and potent drugs. Follow-ing, some other applications are described.

Agonists of the gonadotropin-releasing hormone (GnRH) receptor were amongst the first successful examples of using a peptidomimetic approach to drug design. As determined by structure–activity and conformational studies, the inclusion of a D-amino acid residue in the 6-position of decapeptide

agonist analogs is sufficient to induce a turn conformation e.g. in triptorelin [Trelstar, Debiopharm; Fig. (10-1)], which significantly enhances the biological effect [168]. One highly successful example currently marketed for the treatment of endocrine cancers, Gosarelin [Zoladex, Astra Zeneca; Fig. (10-2)], also includes an aza-glycine mimetic at the C-terminus to improve the stability of the molecule [169].

Koerber et al. [170], defined the active conformation of antagonist deca-peptides by the incorporation of a series of conformationally restricting cyclisations, and the activity of compounds of this type was shown to be dependent on their ability to adopt a turn structure around residues four to eight. Nuclear magnetic resonance (NMR) studies indicate that the exact location of the backbone turn may not be a key feature for receptor binding affinity, provided that the side chains of


the critical amino acids can adopt the proper spatial orienta-tion, which is encouraging for the design of new analogs [171].

Using a combination of turn mimetic design and directed screening, a bicyclic scaffold was discovered which, when appropriately elaborated with both hydrophobic and basic side chains, produced potent type III antagonists [172]. Re-fined solution conformations and SAR of these and other linear and cyclic Complement factor (C5a) antagonists modulators have paved the way for the transition between peptides and type III mimetics analogous to cases described for Somatostatin (SST). Random screening and subsequent hit optimization at Merck produced the C5a antagonist Fig. (10-3). The similarity between the guanidine, spiroindane and cyclohexyl pharmacophore of Fig. (10-3) and the Arg–Trp and cyclohexylalanine side-chains of antagonist peptides such as Fig. (10-4) is indicative of some degree of type III mimicry. The rational design of compound sets that mimic the well-defined turn of the cyclic peptide derivatives ap-pears to be a promising avenue for the development of potent and selective non-peptide C5a modulators for inflammatory diseases. Eli Lilly has patented a family of D–(p-Cl)–Phe–D–Tic-like structures, of which compound Fig. (10-5) is re-ported to have a potency of 8.4 nM [173]. This specific small molecule peptidomimetic melanocortin-4 receptor (MC4R) agonists exhibit little effect on feeding, while having a marked effect on penile erection in rats. In this case, the de-sign of peptidomimetic compounds has made use of the ob-servation that the majority of known non-peptide agonists of peptide hormone receptors share close structural similarity with known antagonists of those receptors [174].

Recent advances in the development of potent and selec-tive peptide and non-peptide ligands are anticipated to help further unravel the roles of class I and II G-protein-coupled receptors (GPCRs) in the pathogenesis of human diseases and to accelerate the clinical use of small molecule mimetics. Peptidomimetic drug discovery of GnRH antagonists, vaso-pressin agonists, neurotensin agonists, C5a, SST modulators and melanocortin-4 agonists illustrates the success of amal-gamating the fields of conformational-based drug-design, site-directed mutagenesis, screening, smart de novo library design and classical medicinal chemistry. The recognition that discreet well-defined secondary structures are involved in the interactions of peptides with receptors has stimulated the development of molecules that mimic or stabilize such pharmacophoric descriptors. Researchers are currently de-veloping many different non-natural oligomers for use in the mimicry of diverse bioactive peptides. Non-natural azapep-tide and peptoid ligands for MHC-II are being developed to help modulate immune system response, and possibly pro-vide therapy for auto-immune disorders. Novel somatostatin analogues incorporating peptoid and -peptide residues have been reported. Helical peptoid mimics of lung surfactant protein C are the first non-natural synthetic replacements reported. Even peptoid-based collagen mimics have been generated. Bianchini et al. [175], designed and synthesized three novel peptidomimetic phosphinate inhibitors and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8 using molecular dynamics (MD) simulation and molecular modeling. Their IC50 values are in the micromolar range, and one of them showed to be the most effective in-

hibitor of MMP-2. The differences in binding affinities for MMP-2 and MMP-8 of the three phosphinates have been rationalized by means of modeling studies and MD simula-tions, also. In order to fully prove therapeutic benefits of Peptide T (ASTTTNYT), which is a fragment of the gp120 envelop protein of the human immunodeficiency virus (HIV), shown to inhibit binding of gp120 to the CD4, Araya et al. [176], tried to design peptidomimetics of the peptide.

Using computational methods, the natural product amygdalin was identified as a prospective peptidomimetic of the peptide and later proved to exhibit a similar chemotactic profile to the peptide that led to the synthesis of a set of amygdalin analogues lacking the cyanide group with im-proved chemotactic profiles. Targeting farnesyltransferase (FT) enzyme has become a promising strategy in cancer therapy in last decade. Transferring a farnesyl from farne-sylpyrophosphate to the thiol of a cysteine side chain of pro-tein residues is catalyzed by FT enzyme. In order to inhibit the activity of farnesyltransferase (FT) enzyme, a genetic neural network (GNN) approach, using radial distribution function descriptors was used by Gonzalez et al. [177] to achieve this goal by a set of 78 thiol and non-thiol pepti-domimetic inhibitors. The caspase (cysteinyl-aspartate prote-ase) family represents a class of intracellular proteases, play-ing a critical role in apoptotic cell death pathways and acti-vation of pro-inflammatory cytokines. Their enzymatic prop-erties are governed by a nearly absolute specificity for sub-strates containing aspartic acid at the P1 site, and by the use of a cysteine side-chain for peptide-bond hydrolysis. Caspase-3 is an attractive target for therapeutic intervention due to have functions in apoptosis, mediating apoptotic cas-cade from the intrinsic and extrinsic activation pathways. Zhang et al. [178] designed a novel peptidomimetic inhibitor of caspase-3, which had the properties of a reversible inhibi-tor, while the P1 site at the C-terminal remains and only L-amino acid has been replaced by D-amino acid. Thrombosis-related disorders such as deep vein thrombosis, pulmonary embolism, and thromboembolic stroke remain a major cause of morbidity worldwide. The limitations associated with cur-rent therapies2 have driven the search for small-molecule direct inhibitors of specific enzymes involved in the coagula-tion cascade. In this regard, inhibitors of both thrombin and factor Xa have attracted considerable recent attention. Nan-termet et al. [179], demonstrated during their experiments that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this pepti-domimetic core was more resistant toward oxidative metabo-lism, it also defeated the metabolic liability associated with the pyrazinones. Smith et al. [180], developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin (isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines) side chains with the required spatial orienta-tion to mimic the conformation of the relevant region of the natural product.

In Type II diabetes mellitus, the most prevalent form of the disease, tissues develop resistance to the actions of insu-lin even though, in most instances, the insulin receptors in those tissues are structurally normal and are in near normal


1

2

Fig. (10). Five applicable peptidomimetic structures.

abundance. One strategy to combat this insulin resistance therapeutically is to maintain insulin receptors (IR) in the active tyrosine-phosphorylated form by inhibiting enzymes that catalyze IR dephosphorylation. Based on substantial evidence that protein tyrosine phosphatase 1B (PTP1B) cata-lyzes IR dephosphorylation and is involved physiologically and pathologically in terminating insulin signaling, this en-zyme has emerged as an attractive therapeutic target. Larsen et al. [181], designed low molecular weight peptidomimetic

compounds based on O-malonyl tyrosine and O-carboxymethyl salicylic acid are potent inhibitors of PTP1B. One member of the family of Signal Transducer and Activa-tor of Transcription (STAT) proteins, Stat3, participates in malignant transformation. The critical role of Stat3 in the growth and survival of human tumor cells provides a valid basis for targeting Stat3 for development of novel inhibitors. Turkson et al. [182], reported novel tripeptide mimics that have been developed for improved selectivity and efficacy

NH

O

H

NH

O

O

NHNH

OOH

NH

O

O

NH

O

O

NH

O

NH

NH

NH

NH2

O

N

H

O NHNH

O

NH2

NHOH

N

NH

NH

O

H

NH

O

O

NHNH

OOH

NH

O

O

NH

O

NH

O

NH

NH

NH

NH2

O

N

H

O NHNH

O

NH2

OH

N

NH

NH

NH

5

ONH

N

O

NH

N

Cl

NS

O

O

4: R=H, n=2

RNH

O

HN

O

N

O

O

NH

N

O

NH

HN

NH2

NH

O

NH

H

H

n

3

NH2

HNNH

N

NH

O

O

O

N


with regard to inhibition of Stat3 activity. The presence of these peptidomimetic compounds in nuclear extracts results in a dose-dependent decrease in the level of Stat3 DNA-binding activity in vitro, with efficacies that are five to ten folds higher than previously obtained for tripeptides.

Hematopoietic growth factors such as G-CSF, M-CSF, GM-CSF and EPO have received considerable attention in recent years. These factors play key roles in regulating cellu-lar host defense mechanisms involved in combating bacte-rial, fungal and viral infections. They stimulate host defense mechanisms by both increasing immunocompetent cell num-bers and enhancing effectors cell functions. The activity of a novel series of peptidomimetic hematoregulatory com-pounds, designed by Heerding et al. [183] based on a phar-macophore model inferred from the structure activity rela-tionships (SAR) of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The com-pounds may represent novel therapeutic agents in the area of hematoregulatio.

The binding and internalization of pathogens by host cells are critical steps in the development of many infectious diseases. Many viruses and bacteria pathogens are capable of exploiting host cell surface integrins during their replication cycles. The integrins are a family of large alpha/beta het-erodimeric membrane proteins that function as cell adhesion and signal transducing molecules affecting proliferation, survival, differentiation, and migration the ligands for many integrins contain an arginine–glycine–aspartic acid (RGD) amino acid sequence that is essential for protein–protein in-teraction. Synthetic peptidomimetics of RGD have been shown to be antagonists of the activities of specific integrins both in vitro and in vivo. Infection of cultured human cells has been shown to be inhibited by RGD-containing peptides. In a study, Hippenmeyer et al. [184], tried to understand if these small molecules are antagonists of adenovirus infec-tion. Their results suggested that integrins interact with ade-noviral RGD in a manner similar to that of other protein ligands such as vitronectin. Furthermore, the results confirm the role of RGD in the replication cycle, and suggest pepti-domimetic compounds may be useful antimicrobial agents in the treatment of a variety of diseases. The phosphoprotein p53 plays a key role in maintaining the genomic integrity of cells.

In response to DNA damage and other types of stress stimuli, p53 causes cell-cycle arrest1 or activates apoptosis. In normal cells, p53 is held in check until needed by the mur-ine double-minute clone 2 (MDM2). Detrimental mutations of p53 are common mechanisms for the loss of p53 wild-type activity in cancer cells.5 But another important mecha-nism is over expression of MDM2, which leads to constitu-tive inhibition of p53; this is commonly seen in cancerous cells containing wild-type (WT) p53. The p53–MDM2 com-plex is a target for anticancer drug design due to its impor-tance in cancer development. It has been shown that a p53 homologue is sufficient to induce p53-dependent cell death in cells over-expressing MDM2. Recently, Zhong et al. [185], used molecular dynamics (MD) simulations in order to design a potent -peptide mimic of p53 mimic based on a tetramer of -proline, a promising peptidomimetic oligomer,

to examine the binding interface and the effect of mutating key residues in the human p53–MDM2 complex.

The blood coagulation cascade is divided into extrinsic and intrinsic coagulation pathways. Factor VIIa (FVIIa) in complex with tissue factor (TF) initiates the extrinsic coagu-lation pathway. Recent studies on blood coagulation have suggested that selective inhibition of extrinsic coagulation provides effective anticoagulation and low risk of bleeding compared with other antithrombotic mechanisms. Thus, spe-cific FVIIa/TF complex inhibition, which blocks only extrin-sic coagulation, is seen as a promising target for developing new anticoagulant drugs. Kadono and co-workers [186], showed that compound 1 (Fig. 1) with the large P3 moiety D-biphenylalanine showed relatively high selectivity against thrombin. They were able to show in other experiment that structure-based designs of the P3 moiety in the pepti-domimetic factor VIIa inhibitor successfully led to novel inhibitors with selectivity for FVIIa/TF and extrinsic coagu-lation the same as or even higher than those of previously reported peptidomimetic factor VIIa inhibitors.

CONCLUSION

Considering the growing rate of fungal infections, and the limitations of current existing therapies, it is widely speculated that the direction of research in the field of devel-oping new agents be revisited and the policies be re-evaluated. The problem of resistance caused by the patho-genic and opportunistic fungal organisms is becoming com-mon in medical practice. The treatment of patients with sub-optimal dosage, delivery issues are part of the wider picture to be considered in this respect. The administered drugs, however, may not reach the target or the target itself may have changed. In instances, where the molecular design needs modification, it is possible to initiate the molecular lead discovery process to present new structural features resistant to degradation by the organism or less prone to re-sistance due to new targets.

The antifungal peptides are part of a category of com-pounds belonging to the larger group of agents called antimi-crobial peptides. One of the common features of this group is paucity of developed resistance which is believed to be partly due to their mechanism of action involving mem-branes. In this group, there are physicochemical features that make them suitable candidates for further development and evaluation. These features were analyzed by our team sepa-rately and reported before [187]. The compounds known as peptidomimetics are capable of carrying the features of AFP compounds they were originated from, without actually pre-senting the disadvantages usually exist in such compounds. In this article, in addition to looking at the latest develop-ments in this field, we tried to surface the potentials of such compounds in drug discovery for infectious diseases. It is evident that the general strategy that would lead to better and more effective peptidomimetic antifungals would depend on the target, types of compound, organism involved, the cell wall and other barriers which may exist on the way of drug penetration [188]. The optimization can be carried out by in silico tools. After all, the availability of building blocks or feasibility of synthetic tools should not be neglected [189]. Although the structural complexity and the above-mentioned


aspects would make the design of such compound difficult, the development of computational tools and the internet servers provide powerful resources for further flourishing of this field.

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Received: June 11, 2009 Revised: August 01, 2009 Accepted: August 01, 2009

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