Ipglycermides Novel potent and selective inhibitors of parasitic phosphoglycerate mutase

National Center For Advancing Translational Sciences

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Abstract

Subtractive genomic analysis identified co-factor independent phosphoglycerate mutase (iPGM) as a potential drug target in several infectious organisms, including parasitic nematodes, trypanosomes and several gram positive bacteria including Staphylococcus aureus. iPGM is an essential glycolytic enzyme in energy production. iPGM has been considered undruggable due to unsuccessful attempts to identify inhibitors from small molecule high throughput screening (HTS) In collaboration with C. Carlow (NEB), H. Suga (U. Tokyo), D. Ross (NIST) and Scott Lovell (U. Kansas) the ADST laboratory has developed strategic alternatives to HTS to target this essential metabolic enzyme of the pathogenic nematode using novel cyclic peptide libraries and affinity selection and enrichment approaches. This project has resulted in the discovery and characterization of Ipglycermides, the first inhibitor class that potently and selectively inhibits iPGM from all nematodes species thus far tested. The pharmacological evaluation of ipglycermide analogs and the binding site interaction revealed from a co-crystal structure will provide general molecular insights for the development of therapeutics to highly dynamic proteins generally refractory toward inhibition by small molecule ligands.