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International research identifies potential anti-microbial drug
April 23, 2017, 1:30 pm
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Research teams from the National Institutes of Health in the United States, the University of Tokyo and other international research institutions have identified the first inhibitor of an enzyme long thought to be a potential drug target for fighting disease-causing parasites and bacteria.

The teams, led by NIH's National Center for Advancing Translational Sciences (NCATS) and University of Tokyo scientists, sorted through more than one trillion small protein fragments called cyclic peptides to uncover two that could shut down the enzyme. The finding could set the stage for the potential development of new types of antimicrobial drugs that could have potential impact on the lives of millions of people worldwide.

The target enzyme, called cofactor-independent phosphoglycerate mutase (iPGM), is found in both parasites and bacteria. Several types of parasitic roundworms have iPGM, including those that cause devastating infectious diseases, such as lymphatic filariasis and river blindness, which affect over 150 million people living in mostly tropical regions. The enzyme is also found in bacteria, including Staphylococcus aureus, which can cause the hospital-borne infection MRSA (methicillin-resistant Staphylococcus aureus), and Bacillus anthracis, which causes anthrax.

iPGM is one of many essential enzymes the roundworm needs to survive. Enzymes are proteins that jumpstart chemical reactions and IPGM is part of a common biological process called glycolysis, which helps make energy for cells. While the same important process occurs in human cells, it relies on a different form of the enzyme. As a result, a drug that targets iPGM and kills the roundworm would likely leave the human counterpart alone.

However, previous attempts by researchers at finding a compound to block the enzyme have failed mainly on account of target sites on the surface of iPGM being short-lived. Because of the enzyme's unusual design, the reserch team sought a different type of drug than the typical small molecule drugs.

The researchers built a library mixture of more than 1 trillion small peptides and then went a step further by adding an amino acid to the peptides to create ring-shaped cyclic peptides. The scientists hypothesized this would have the needed shape and structure to attach to the enzyme surface and disable the enzyme. The researchers sifted repeatedly through millions of cyclic peptides before eventually finding two cyclic peptides that bound tightly to only the iPGM enzyme and also shut down its activity.

Current anti-parasitic drugs, such as ivermectin, mainly work on the early larval stages of the worm and the treatment must be given annually or semiannually for as long as a decade. For years, scientists have tried to find a more effective drug that also worked against the adult worm and the later stages of infection.

The team behind the research said the inhibitor peptides they found and dubbed 'ipglycermides', which might work on all life stages of the worm, could become a broad spectrum anti-parasitic and anti-bacterial treatment that could be delivered acutely, akin to an antibiotic.

The group's next steps will be to find ways for cyclic peptides to enter cells. "If we can find ways to put cyclic peptides into cells, then this would open up new targets that small molecule drugs have a difficult time addressing. Ipglycermides represent a fertile yet uncultivated landscape between small molecule drugs and protein biologics,” said the researchers.

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