Development of Small Molecule Inhibitors of Entamoeba histolytica MTA Nucleosidases (MTNs)
Additional Funding Sources
MBM is the recipient of an LSAMP summer research fellowship. This project was supported by NIH grant 1R15GM125065-01 to KC and JT. The project was also supported by the NIH NIGMS IDeA Program under Grants Nos. P20GM103408 and P20GM109095, the Boise State Biomolecular Research Center, and the Institute for Translational Health Sciences (ITHS). LSAMP funding provided by the Pacific Northwest Louis Stokes Alliance for Minority Participation through the National Science Foundation under Award No. HRD-1410465.
Abstract
Entamoeba histolytica is a parasitic protozoan that causes 50,000-100,000 deaths annually, and untold millions of cases of severe dysentery, mostly in developing countries. The incidence and severity has increased due to the recent emergence of chronic infections and drug-resistant parasite strains. This underscores the need to develop new anti-parasitic drugs with novel targets within the parasite. The Entamoeba enzyme 5’ Methylthioadenosine Nucleosidase (EH MTN) is a potential target since it is required to salvage essential adenine and methionine required for parasite survival. In this study, we examined a series of non-nucleoside small molecule inhibitors (SMIs) of EH MTN that were initially identified by in silico screening against the known E. coli MTN enzyme structure. The results of our work show that a number of the inhibitors exert low micromolar inhibition constants, and are potential lead compounds for further drug development.
Development of Small Molecule Inhibitors of Entamoeba histolytica MTA Nucleosidases (MTNs)
Entamoeba histolytica is a parasitic protozoan that causes 50,000-100,000 deaths annually, and untold millions of cases of severe dysentery, mostly in developing countries. The incidence and severity has increased due to the recent emergence of chronic infections and drug-resistant parasite strains. This underscores the need to develop new anti-parasitic drugs with novel targets within the parasite. The Entamoeba enzyme 5’ Methylthioadenosine Nucleosidase (EH MTN) is a potential target since it is required to salvage essential adenine and methionine required for parasite survival. In this study, we examined a series of non-nucleoside small molecule inhibitors (SMIs) of EH MTN that were initially identified by in silico screening against the known E. coli MTN enzyme structure. The results of our work show that a number of the inhibitors exert low micromolar inhibition constants, and are potential lead compounds for further drug development.
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