Covalent Targeting of Ras G12C by Rationally Designed Peptidomimetics

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 noncovalent contacts but have the inherent risk of dominating noncovalent contacts and increasing the likelihood of nonselective binding. Here, we report the iterative design of a proteolytically stable α₃β chimeric helix mimic that covalently targets oncogenic Ras G12C 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 signaling cascade, and is selectively toxic toward mutant Ras G12C 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.