ACS Chemical Biology 2020
DOI: 10.1021/acschembio.0c00204
Protein-protein interactions (PPIs) play a critical role in fundamental biological processes. Competitive inhibition of these interfaces requires compounds that can access discontinuous binding epitopes along a large, shallow binding surface area. Conformationally- defined protein surface mimics present a viable route to target these interactions. However, the development of minimal protein mimics that engage intracellular targets with high affinity remains a major challenge because mimicry of a portion of the binding interface is often associated with the loss of critical binding interactions. Covalent targeting provides an attractive approach to overcome the loss of non-covalent contacts but have the inherent risk of dominating non-covalent contacts and increasing the likelihood of non-selective binding. Here, we report the iterative design of a proteolytically-stable helix mimic that covalently targets oncogenic G12C Ras as a model system. We explored several electrophiles to optimize preferential alkylation with the desired C12 on Ras. The designed lead peptide modulates nucleotide exchange, inhibits activation of the Ras-mediated signalling cascade, and is selectively toxic towards mutant G12C Ras cancer cells. The relatively high frequency of acquired cysteines as missense mutations in cancer and other diseases suggests that covalent peptides may offer an untapped therapeutic approach for targeting aberrant protein interactions.
