International scientific teams find potentialapproach against parasites3 April 2017

The cyclic peptide ipglycermide binds to an iPGMenzyme, blocking its activity. Credit: Jim Inglese, NCATS

Research teams from the National Institutes ofHealth and abroad have identified the first inhibitorof an enzyme long thought to be a potential drugtarget for fighting disease-causing parasites andbacteria. The teams, led by NIH's National Centerfor Advancing Translational Sciences (NCATS)and University of Tokyo scientists, sorted throughmore than 1 trillion small protein fragments calledcyclic peptides to uncover two that could shutdown the enzyme. The finding, reported April 3,2017 in Nature Communications, could set thestage for the potential development of new types ofantimicrobial drugs.

NCATS' expertise in early stage, pre-clinicalmolecule discovery helped the teams find potential drug candidates that could have implications formillions of people worldwide.

"The work is an excellent demonstration of howNCATS delivers on its mission to provide

improvements in translational processes," saidAnton Simeonov, Ph.D., scientific director, NCATSDivision of Pre-Clinical Innovation. "Scientists haveshown that a therapeutic target, previouslyconsidered undruggable by pharmaceuticalcompanies, is actually druggable through a non-traditional therapeutic agent."

The target enzyme, cofactor-independentphosphoglycerate mutase (iPGM), is found in bothparasites and bacteria. Several types of parasiticroundworms have iPGM, including Brugia malayiand Onchocerca volvulus, which infect roughly 150million people living mostly in tropical regions.These parasites can cause devastating infectiousdiseases, such as river blindness. The enzyme alsois found in bacteria, including Staphylococcusaureus, which can cause the hospital-borneinfection MRSA (methicillin-resistantStaphylococcus aureus), and Bacillus anthracis,which causes anthrax.

"Several infectious organisms are potentiallysusceptible to an iPGM inhibitor," said co-corresponding author James Inglese, Ph.D.,director, NCATS Assay Development andScreening Technology Laboratory. "The teamdubbed the inhibitor peptides 'ipglycermides,' whichrepresent a powerful class of iPGM inhibitors. Intheory, such a drug could become a broadspectrum anti-parasitic and anti-bacterialtreatment."

Current anti-parasitic drugs, such as ivermectin,mainly work on the early larval stages of the worm.Such a treatment must be given annually orsemiannually for as long as a decade. For years,scientists have tried to find a more effective drugthat also worked against the adult worm and thelater stages of infection. Earlier studies by Inglese'scollaborators at New England Biolabs in Ipswich,Massachusetts, showed that iPGM is one of manyessential enzymes the roundworm needs tosurvive. It is part of a common biological process

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called glycolysis, which helps make energy for cells.While the same important process occurs in humancells, it relies on a different form of the enzyme. Asa result, a drug that targets iPGM and kills theroundworm would likely leave the humancounterpart alone. Such a drug might work on alllife stages of the worm, and the infection couldpossibly be treated acutely, akin to an antibiotic.However, their previous attempts at finding acompound to block the enzyme have failed.

Enzymes are proteins that jumpstart chemicalreactions. Most enzymes have pocket-shaped"active sites" into which a molecule fits, and onwhich the enzyme acts. Small molecule drugs canfit in active sites and prevent, or inhibit, the enzymefrom doing its biological job. But iPGM and othersimilar enzymes are different. iPGM has a short-lived, temporary active site, making it practicallyimpossible to find a small molecule drug that canblock the enzyme.

Because of the enzyme's unusual design, theNCATS-led team sought a different type of drugthan the typical small molecule drugs. Inglesecollaborated with co-corresponding author HiroakiSuga, Ph.D., at the University of Tokyo, to build alibrary mixture of more than 1 trillion small peptides.The team went one step further, adding an aminoacid to the peptides to create ring-shaped cyclicpeptides, which the scientists hypothesized wouldhave the needed shape and structure to attach tothe enzyme surface and disable the enzyme.

The researchers sifted repeatedly through thecyclic peptides to find which would stick most tightlyto the enzyme. They found two cyclic peptides thatboth bound tightly to only the iPGM enzyme andalso shut down its activity.

The team subsequently worked with structuralbiologists at the University of Kansas, Lawrence, todetermine the structure of the iPGM-cyclic peptidearrangement, showing how the peptide preventedthe enzyme from working properly. "The cyclicpeptide has amazingly tight and selective affinity foriPGM, like an antibody," Inglese said.

The group's next steps will be to find ways for cyclicpeptides to enter cells. "If we can find ways to put

cyclic peptides into cells, then this would open upnew targets that small molecule drugs have adifficult time addressing," Inglese said."Ipglycermides represent a fertile yet uncultivatedlandscape between small molecule drugs andprotein biologics."

Provided by National Institutes of Health

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APA citation: International scientific teams find potential approach against parasites (2017, April 3)retrieved 2 November 2021 from https://phys.org/news/2017-04-international-scientific-teams-potential-approach.html

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