Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.

ABSTRACT: The papain-like protease (PL^Pro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PL^Pro led to the identification of a novel class of spiro[chromane-2,4'-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PL^Pro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC₅₀ = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC₅₀ = 2.1 μM at 48 hpi). This novel class of inhibitors repr

SUBMITTER: Wei Q 

PROVIDER: S-EPMC12910659 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature