Ipglycermides Novel potent and selective inhibitors of parasitic phosphoglycerate mutase

National Center For Advancing Translational Sciences

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Abstract

This project has advanced from our Target-based Assays and Screening Strategies for Chemical Probe and Therapeutic Lead Discovery category. In continued and expanded collaboration with Prof. H. Suga (U. Tokyo) and his colleagues, Prof. C. Hoffman (Boston College), Prof. S. Lovell (U. Kansas), and W. Vreeland (NIST) the ADST laboratory has developed peptide macrocycles targeting this essential metabolic enzyme of the pathogenic nematode using novel cyclic peptide libraries and affinity selection and enrichment approaches. Analogs and formulations are now being investigated to advance the agent for testing in cellular and pathogenic organism model systems. The work describing the initial phase of this project was published in 2017. 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. Additionally, the development of macrocyclic peptide building blocks being evaluated in the context of this program have resulted in novel iPGM inhibitor macrocyclic pharmacophores. A model organism C. elegans system is being developed to test the activity of membrane permeable analogs on the viability of the organism. The binding site interaction revealed from several co-crystal structures have provided general molecular insights for the design of analogs now being evaluated in across a panel of iPGM orthologs with the eventual aim to evaluate in the secondary cell and model organism assays now under development. Ipglycermide macrocyclic peptide chemotypes have now been extended to prokaryotic infectious organism iPGMs N-methyl amide containing ipglycermides, more proteolytically resistant have been generated.