Potent and Selective Cyclic Peptide Inhibitors of Phosphoglycerate Mutase as Anti-Infective Agents

Summary – The invention includes compounds and compositions for inhibiting phosphoglycerate mutase (PGM) activity. In some examples, the compounds selectively inhibit cofactor-independent PGM (iPGM). In particular embodiments, the compounds include one or more cyclic peptides.

Brief Background – Co-factor independent phosphoglycerate mutase (iPGM) is an essential glycolytic enzyme and validated target in several infectious organisms structurally distinct from its human isozyme. iPGM, present in several types of parasitic roundworms, including Brugia malayi and Onchocerca volvulus, infects roughly 150 million people living mostly in tropical regions. The parasites can cause devastating infectious diseases, such as river blindness. The enzyme also is found in bacteria, including Staphylococcus aureus, which can cause the hospital-borne infection MRSA (methicillin-resistant Staphylococcus aureus), and anthrax. However, the enzyme has been considered “undruggable” due to unsuccessful attempts to identify inhibitors suitable for development from small molecule high throughput screening (HTS). As an alternative approach to HTS the exceedingly vast chemical space available from nucleic acid-encoded cyclic peptide libraries was used to isolate a potent and selective iPGM inhibitor class, called Ipglycermides.

Technical Description – mRNA-display affinity selection was used to identify, enrich and decode high-affinity iPGM cyclic peptide ligands we termed Ipglycermides. Using solid phase peptide synthesis the ipglycermides and analogs were prepared in milligram quantity and evaluated in functional target-based assays on a panel of phosphoglycerate mutase enzymes from target and anti-target (i.e., human dPGM) species. The molecules were found to potently and selectively inhibit the catalytic activity of various microorganism iPGMs versus the human isozyme. The pharmacological evaluation of ipglycermide analogs and the binding site interaction revealed from an iPGM-ipglycermide co-crystal structure provide general molecular insights for the development of a therapeutic targeting this highly dynamic protein hereto now refractory toward inhibition by traditional small molecule ligands.

Potential Commercial Applications: Competitive Advantages:
  • Anti-parasitic
  • Select antibacterial
  • NCATS, University of Tokyo and New England Biolabs researchers identified cyclic peptide inhibitors of the enzyme 2,3-bisphosphoglycerate-independent phosphoglycerate mutase (ipgm-1) that could treat both parasitic and bacterial infections.


James Inglese (NCATS)  ➽ more inventions...

Patricia Dranchak (NCATS)  ➽ more inventions...

Ryan Macarthur (NCATS)  ➽ more inventions...

Intellectual Property:
US Pat: 10,808,010 issued 2020-10-20
PCT Application No. PCT/US2017/046228 filed on 2017-08-10
US Application No. 16/324,424 filed on 2019-02-08
US Application No. 17/016,168 filed on 2020-09-09

Crowther GJ, et al. PMID 24416464
Yu H, et al. PMID 28368002

Collaboration Opportunity:

Researchers at the NCATS seek licensing and/or co-development research collaborations for development of Ipglycermide as a broad-acting anti-microbial and anti-parasitic agent. A focus on any one of a number of infectious organisms would be of interest.

Inventor Expectations for Collaborators: To expand our effort to additional pathogenic organisms dependent on iPGM with appropriate pre-clinical in vivo model systems and lead development capability.

Licensing Contact:
Rebecca Erwin-Cohen, Ph.D.
Email: rebecca.erwin-cohen@nih.gov
Phone: 301-827-7235

OTT Reference No: E-229-2016-0
Updated: Apr 26, 2017