الرحيم الرحمن الله بسم

MEDICAL MICROBIOLOGY

Chapter 35 Antiviral Drugs

Introduction the number of antiviral drugs is very small BECAUSE:

1 \the difficulty in obtaining selective toxicity against viruses.

2 \they are relatively ineffective because many cycles of viral replication occur during the incubation period when the patient is well.

3 \Another potential limiting factor is the emergence of drug-

resistant viral mutants.

MECHANISM ( SITE) OF ACTIONTable 35–1. Potential Sites for Antiviral Chemotherapy

Site of ActionEffective DrugsEarly events (entry or uncoating of the virus)

Amantadine, rimantadine, enfuvirtide, maraviroc

Nucleic acid synthesis by viral DNA and RNA polymerases

Acyclovir, valacyclovir, valganciclovir

Integrase that integrates HIV DNA into cellular DNA

Raltegravir

Cleavage of precursor polypeptides

Saquinavir, indinavir, ritonavir, nelfinavir

Protein synthesis directed by viral mRNA

Interferon, fomivirsen, methisazone

Action of viral regulatory proteins

None

Assembly of the virus, including the matrix protein

None

Release of the virusZanamivir, oseltamivir

Inhibition of Early Events adamantanamine

1\adamantanamine, three-ring compound virus

2\It prevents replication by inhibiting uncoating of the virus

3\transcription by the virion RNA polymerase does not because uncoating cannot occur

4\This drug specifically inhibits influenza A virus; influenza B and C viruses are not affected

5\it is not widely used in the United States

6\main side effects of amantadine are central nervous system alterations such as dizziness, ataxia

7\Rimantadine (Flumadine) is a derivative of amantadine and has the same mode of action but fewer side effects .

Enfuvirtide:

1 \Enfuvirtide is a synthetic peptide that binds to gp41 on the surface of the virion

2 \block the entry of human immunodeficiency virus (HIV) into the cell

3\It is the first of a new class of anti-HIV drugs known as "fusion inhibitors

Inhibition of Viral Nucleic Acid Synthesis 1-Inhibitors of Herpesviruses

*Nucleoside Inhibitors1\These drugs are analogues of nucleosides

2\inhibit the DNA polymerase of one or more members of the herpesvirus family. Acyclovir

1 \Acyclovir (acycloguanosine, Zovirax) is a guanosine analogue that has a three-carbon.

2 \Acyclovir is active primarily against HSV-1 and -2 and varicella-zoster virus (VZV).

3 \it is activated preferentially within virus-infected cells. This is due to the virus-encoded thymidine kinase, which phosphorylates acyclovir much more effectively than does the cellular thymidine kinase

4 \cellular kinases synthesize acyclovir triphosphate, which inhibits viral DNA polymerase much more effectively than it inhibits cellular DNA polymerase.

5\Acyclovir causes chain termination because it lacks a hydroxyl group in the 3' position.

6 \It has no activity against CMV.

Figure 35–2

It has selective action because

1\Acyclovir is phosphorylated to acyclovir monophosphate much more effectively by herpesvirus-encoded thymidine kinase than by cellular

thymidine kinase.

preferentially activated in herpesvirus-infected cells and much less so in uninfected cells.

2\Acyclovir triphosphate inhibits herpesvirus-encoded DNA polymerase much more effectively than it does cellular DNA polymerase.

inhibits viral DNA synthesis to a much greater extent than cellular DNA synthesis

Indication 1 \Topical acyclovir is effective in the treatment of primary

genital herpes and reduces the frequency of recurrences while it is being taken

2 \Acyclovir is the treatment of choice for HSV-1 encephalitis

3 \effective in preventing systemic infection by HSV-1 or VZV in immunocompromised patients

Notes: - Acyclovir-resistant mutants have been isolated from

HSV-1- and VZV-infected patients. Resistance is most often due to mutations in the gene encoding the viral

thymidine kinase.

cont

-Acyclovir is well-tolerated and causes few side effects-Intravenous acyclovir may cause renal or central nervous

system toxicity-Derivatives of acyclovir with various properties are now

available1-Valacyclovir (Valtrex) achieves a high plasma

concentration when taken orally 2 -Penciclovir cream (Denavir) is used in the treatment of

recurrent orolabial herpes simplex 3-Famciclovir (Famvir) when taken orally is converted to

penciclovir and is used to treat herpes zoster and in herpes simplex infections

Ganciclovir

1\Gancicloviris a nucleoside analogue of guanosine with a four-carbon fragment

2\It is structurally similar to acyclovir but is more active against CMV than is acyclovir

3 \Ganciclovir is activated by a CMV-encoded phosphokinase in a process similar to that by

which HSV activates acyclovir

Indication

1\drug of choice in the treatment of retinitis caused by CMV in AIDS patients

2\may be useful in other disseminated infections, such as colitis and esophagitis

Side effect bone marrow suppression

leukopenia and thrombocytopenia

note\ Valganciclovir, which can be taken orally, is also effective against CMV retinitis

Cidofovir 1 \Cidofovir is a nucleoside analogue of cytosine

that lacks a ribose ring

Indication

1 \treatment of retinitis caused by CMV2 \in severe human papillomavirus infections

3 \treatment of severe molluscum contagiosum in immunocompromised patients

Note\ Kidney damage is the main side effect .

Vidarabine 1\Vidarabine is a nucleoside analogue with arabinose in

place of the normal sugar, ribose..

2\the drug is phosphorylated by cellular kinases to the triphosphate.

inhibits the herpesvirus-encoded DNA polymerase more effectively than the cellular DNA polymerase

3\Vidarabine is effective against HSV-1 infections such as encephalitis and keratitis.

Note \ it is less effective and more toxic than acyclovir.

Iododeoxyuridine 1 \Iododeoxyuridine (idoxuridine, IDU, IUDR) is a nucleoside analogue in which

the methyl group of thymidine is replaced by an iodine atom

2 \The drug is phosphorylated to the triphosphate by cellular kinases and incorporated into DNA

3\It is clinically useful in the topical treatment of keratoconjunctivitis caused by herpes simplex virus

Note \Because IDU has a high frequency of mismatched pairing to guanine, it causes the formation of faulty progeny DNA and mRNA

IDU is incorporated into normal cell DNA as well as viral DNA

it is too toxic to be used systemically

Trifluorothymidine 1 \Trifluorothymidine (trifluridine, Viroptic) is a

nucleoside analogue in which the methyl group of thymidine contains three fluorine atoms instead of three hydrogen atoms

2 \Its mechanism of action is probably similar to that of IDU

3 \it is too toxic for systemic use but is clinically useful in the topical treatment of keratoconjunctivitis ( drug of choice) caused by

herpes simplex virus

*Non-Nucleoside Inhibitors

These drugs inhibit the DNA polymerase of herpesviruses by mechanisms distinct from the

nucleoside analogues described above.

Foscarnet 1 \Foscarnet M,unlike the previous drugs which are nucleoside

analogues, is a pyrophosphate analogue 2 \It binds to DNA polymerase at the pyrophosphate cleavage site and

prevents removal of the phosphates from nucleoside triphosphates (dNTP).

This inhibits the addition of the next dNTP and, as a consequence, the extension of the DNA strand.

3 \Foscarnet inhibits the DNA polymerases of all herpesviruses, especially HSV and CMV.

4 \it does not require activation by thymidine kinase. Foscarnet also inhibits the reverse transcriptase of HIV

Indication

1\It is useful in the treatment of retinitis caused by CMV

2 \Foscarnet is also used to treat patients infected with acyclovir-resistant mutants of HSV-1 and VZV.

2\Inhibitors of Retroviruses

* Nucleoside Inhibitors The selective toxicity of (azidothymidine, dideoxyinosine, dideoxycytidine, d4T, and 3TC) is based on their ability to inhibit DNA synthesis by the reverse transcriptase of HIV to a much greater extent than they inhibit DNA synthesis by the DNA polymerase in human cells. The effect of these drugs on the replication of HIV is depicted

in Figure 45–3.

Azidothymidine

1 \Azidothymidine (zidovudine, Retrovir, AZT) is a nucleoside analogue that causes chain termination during DNA synthesis

2 \It is particularly effective against DNA synthesis by the reverse transcriptase of HIV and inhibits growth of the

virus in cell culture.

3 \It is currently the drug of choice in patients with AIDS Note\ The main side effects of AZT are bone marrow suppression and myopathy.

Dideoxyinosine

1 \Dideoxyinosine (didanosine, Videx, ddI) is a nucleoside analogue that causes chain termination during DNA synthesis

2 \The administered drug ddI is metabolized to ddATP, which is the

active compound

3 /It is effective against DNA synthesis by the reverse transcriptase of HIV and is used to treat patients with AIDS who are intolerant of or resistant to AZT

Note/ The main side effects of ddI are pancreatitis and peripheral neuropathy .

*Dideoxycytidine like Dideoxyinosine

Stavudine

1 /Stavudine (d4T, Zerit) is a nucleoside analogue that causes chain termination during DNA

synthesis.

2 /It inhibits DNA synthesis by the reverse transcriptase of HIV and is used to treat patients with advanced AIDS who are intolerant of or resistant to other approved therapies Note/ The main side effect is peripheral

neuropathy

Lamivudine

1 /Lamivudine (3TC, Epivir) is a nucleoside analogue that causes chain termination during DNA synthesis by the reverse transcriptase of HIV

2 /When used in combination with AZT, it is very effective both in reducing the viral load and in elevating the CD4

cell count.

3 /Lamivudine is also used in the treatment of chronic hepatitis B. Note/

*It is one of the best-tolerated of the nucleoside inhibitors *side effects such as neutropenia, pancreatitis, and

peripheral neuropathy do occur.

Abacavir

1 /Abacavir (Ziagen) is a nucleoside analogue of guanosine that causes chain termination during DNA synthesis.

2 /Abacavir is used in combination with either a

protease inhibitor or AZT plus lamivudine. Note/ It is available through the "expanded access" program to those who have failed currently available drug regimens

Tenofovir 1 /Tenofovir (Viread) is an acyclic nucleoside

phosphonate that is an analogue of adenosine monophosphate. It is a reverse transcriptase inhibitor that acts by chain termination

2 /It should be used in combination with other anti-HIV drugs.

Note / It is approved for use in patients who have developed resistance to other reverse transcriptase inhibitors and in those who are starting treatment for the first time

*Non-Nucleoside Inhibitors 1 \the drugs in this group are not nucleoside analogues and

do not cause chain termination.

2 \act by binding near the active site of the reverse transcriptase and inducing a conformational change that inhibits the synthesis of viral DNA.

3 \NNRTIs should not be used as monotherapy because

resistant mutants emerge rapidly.

4 \Strains of HIV resistant to one NNRTI are usually resistant to others as wel.

Nevirapine(dipyridodiazepinones) 1 \Nevirapine (Viramune) is usually used in

combination with zidovudine and didanosine

2 \There is no cross-resistance with the nucleoside inhibitors of reverse transcriptase described above

3 \The main side effect of nevirapine is a severe skin rash

)Stevens-Johnson syndrome(

Delavirdine bisheteroarylpiperazines( )

1 \Delavirdine (Rescriptor) is effective in combination with either zidovudine or zidovudine plus didanosine

Efavirenz(benzoxazin-2-ones )

1\Efavirenz (Sustiva) in combination with zidovudine plus lamivudine was more effective and better tolerated than the combination of indinavir, zidovudine, and lamivudine

2\The most common side effects are referable to the central nervous system, such as dizziness,

insomnia, and headaches .

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