Journal of medicinal chemistry · 2026
Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.
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Wei Qiangqiang, Taylor Ashley J, Miriyala Nagaraju, Barmade Mahesh A, Gentry Zachary O, Anderson-Daniels Jordan, Teuscher Kevin B, Crow Mackenzie M, Apakama Chideraa, South Taylor M, Rietz Tyson A, Amporndanai Kangsa, Phan Jason, Sensintaffar John L, Denison Mark, Lee Taekyu, Fesik Stephen W
Аннотация
The papain-like protease (PLPro) 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 PLPro 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 PLPro 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 represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.