Activated immune cells produce both nitric oxide and several aldehydes. The H. Darwin lab has found that nitric oxides and aldehydes exhibit synergistic killing of M. tuberculosis in vitro, and we hypothesize that this effect contributes to pathogen control in vivo. In order to elucidate the mechanism of this toxicity we initiated a genetic screen for resistant mutants, and have now validated three genes from this screen, including two metabolic enzymes and a transcriptional regulator.

Description: Protein-protein interactions (PPIs) play a critical role in fundamental biological processes, ranging from intracellular signaling to programmed cell death. We have previously developed an orthosteric inhibitor of the Ras-Sos interaction by employing an alpha-helical mimic of the Sos alphaH helix. To further enhance overall specificity and potency, we have developed covalent covalent HBS peptides that can irreversibly link with a specific nucleophile in proximity to the binding site. The oncogenic Ras G12C mutant provides an excellent model platform for testing our designs.