Impact of Single Halogen Atom Substitutions on Antiviral Profile of Inhibitors Targeting SARS-CoV‑2 Main Protease.

ABSTRACT: The SARS-CoV-2 main protease (M^pro) remains a prime antiviral target because its inhibition halts viral replication. To probe how subtle atomic changes influence drug performance, we carried out a systematic halogen scan on a potent ketoamide scaffold, replacing a single fluorine with chlorine, bromine, or iodine. Enzymatic assays revealed that the F- and Cl-substituted analogues inhibit M^pro at nanomolar levels, whereas Br and I variants are 10- to 20-fold weaker. Cell-based antiviral tests mirrored this trend, yet uptake studies showed the opposite: iodine markedly enhances intracellular accumulation. High-resolution X-ray structures (1.6-1.8 Å) explain the dichotomy: small halogens fit snugly in the S1' σ-hole pocket, maximizing hydrogen-bond geometry, while bulkie

SUBMITTER: Bulut H 

PROVIDER: S-EPMC12854628 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature