CNRS / Institut de Biologie Structurale and Harvard Medical School

Start : November 2016 | Status : Active

The scientist: Dr. Hugo Duarte de Carvalho Fraga is a biochemist with extensive experience in enzymology and structural biology. Hugo obtained his PhD in 2007 from the department of chemistry of the Faculdade de Ciências da Universidade do Porto. In 2015, Hugo joined the Goldberg Lab at Harvard Medical School to work on mycobaterial ClpP1P2 complexes.

The sponsor: Institut de Biologie Structurale, CNRS and Department of Cell Biology, Harvard Medical School.

Foundation funding: The Foundation is providing £116,417 in support, together with co-funding from the European Union´s FP7 program through its COFUND scheme.

GSK’s contribution: GSK is providing expertise and know-how on post-screening processes, including hit characterization, medicinal chemistry and enzymology

Project Description: About 10 million people worldwide fall ill from tuberculosis every year, and it has been estimated that one third of all humans is infected with latent Mycobacterium tuberculosis (Mtb). Moreover, Mtb has become increasingly resistant to available antibiotics. Consequently, it is important to identify and characterize new therapeutic targets in Mtb and to synthesize selective inhibitors. ClpP1, ClpP2 and their associated chaperones, ClpX and ClpC1 are required both for the growth of Mtb and for its virulence during murine infection and are highly attractive drug targets, especially since they are not present in the cytosol of mammalian cells, and they differ markedly from the mitochondrial ClpP complex.

The purpose of this projects is to characterize hits from the HTS being conducted at the Open Lab to discover compounds able to inhibit protein degradation by the ClpC1P1P2 complex, and to determine their mode of action. The binding site and structural effects of the hits in ClpC1, ClpX and CpP1P2 will be evaluated using state of art NMR approaches. This project results from collaboration between the Goldberg Lab, Harvard Medical School (HMS) and the Institut de Biologie Structurale (IBS), Grenoble, France and should promote the development of more potent drug candidates.