Starting from our previous finding of 14 known drugs as inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to Mpro. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.

Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts, and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Non-covalent inhibitors of the main protease (M pro ) of SARS-CoV-2 having a pyridinone core were previously reported with IC 50 values as low as 0.018 μM for inhibition of enzymatic activity and EC 50 values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M pro and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC 50 values as low as 0.080 μM, while remdesivir yields values of 0.5–2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds 19 and 21 are particularly promising as potential therapies for COVID-19, featuring IC 50 values of 0.044–0.061 μM, EC 50 values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.

We report the development of a method to parameterize and predict the performance of structurally flexible β-turn-containing peptide catalysts, using the atroposelective bromination of 3-arylquinazolin-4(3H)-ones as a case study. The multivariate correlations obtained for tetrapeptides of two β-turn types, type I′ pre-helical and type II′ β-hairpin, indicate that while one conformer may be associated with a more dominant contribution to the observed enantioselectivity, it is possible that multiple conformers contribute to a complex transition state ensemble.

Studying the relationship between catalyst conformational dynamics and selectivity in an asymmetric reaction is a challenge. In this study, cyclic peptides were computationally designed to stabilize different ground state conformations of a highly effective, flexible tetrapeptide catalyst for the atroposelective bromination of N-aryl quinazolinones. Through a combination of computational and experimental techniques, we have determined that dynamic movement of the lead catalyst plays a crucial role in achieving high enantioselectivity in the reaction of study. This approach may also serve as a valuable method for investigating the mechanism of other peptide-catalyzed transformations.