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.