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Our lab is focused on evaluation of Methionine Aminopeptidase inhibitor Libraries in Leishmania major. N-terminal processing of proteins is an essential process in all organisms. Therefore, inhibiting MetAP function will shed light on the physiological role of MetAP in parasite microbiology and facilitate the future design of novel anti-parasitic agents. I am particularly well-suited to be a collaborating PI on this grant. I have the expertise, background and insight necessary to successfully collaborate on this project. I have a well-rounded background in molecular biology, chemical biology, pharmacology and synthetic chemistry both in industry and academia which are the fundamental skills necessary to lead, implement and successfully complete this project. While I was at Johns Hopkins University School of Medicine, I successfully cloned, over-expressed and purified to near homogeneity the two MetAPs from M. tuberculosis as described in the publication in Chemistry & Biology (3); and the only MetAP in E. faecalis. Using a High-throughput screening approach, I screened a library of 175,000 structurally diverse small molecules and identified novel potent inhibitors of these MetAPs that show either selective or cross-reactive activity relative to host MetAPs. In addition, as a graduate student in collaboration with Dr. Brian Mathews at the University of Oregon, we solved and published the first X-ray structure of MtMetAP1c from Mtb (5). Moreover, in collaboration with the Johns Hopkins TB Research Center I successfully validated some of the TB MetAP inhibitors using a chemical genomics approach. Prior to starting graduate school, I worked in at Merck Research Laboratories and Bristol-Meyers Squibb (4) on projects aimed at the synthesis and the design of potential drug candidates for testing in biological assays. Because of all these past experiences, I have had the exposure to many critical steps involved in drug discovery and the importance of multidisciplinary collaborations and communication. Therefore, I have established collaborations with Dr. Rosa Maldonado at UT El Paso to evaluate the MetAP inhibitors in in vitro and in vivo models of infection. Together, we have a well-rounded collaborative team with expertise that will successfully accomplish the proposed study. We have made recent progress in identifying novel MetAP inhibitors with activity against L. Major. This promising result will give us more insight to the relevance of N-terminal protein processing in L. Major.
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