tetano
Editor, Senior Moderator
J Med Chem
. 2026 Feb 2.
doi: 10.1021/acs.jmedchem.5c03704. Online ahead of print.
Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease
Qiangqiang Wei[SUP] 1 [/SUP], Ashley J Taylor[SUP] 1 [/SUP], Nagaraju Miriyala[SUP] 1 [/SUP], Mahesh A Barmade[SUP] 1 [/SUP], Zachary O Gentry[SUP] 1 [/SUP], Jordan Anderson-Daniels[SUP] 2 [/SUP], Kevin B Teuscher[SUP] 1 [/SUP], Mackenzie M Crow[SUP] 1 [/SUP], Chideraa Apakama[SUP] 1 [/SUP], Taylor M South[SUP] 1 [/SUP], Tyson A Rietz[SUP] 1 [/SUP], Kangsa Amporndanai[SUP] 1 [/SUP], Jason Phan[SUP] 1 [/SUP], John L Sensintaffar[SUP] 1 [/SUP], Mark Denison[SUP] 2 [/SUP], Taekyu Lee[SUP] 1 [/SUP], Stephen W Fesik[SUP] 1 3 4 [/SUP]
Affiliations
The papain-like protease (PL[SUP]Pro[/SUP]) 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[SUP]Pro[/SUP] 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[SUP]Pro[/SUP] inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC[SUB]50[/SUB] = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC[SUB]50[/SUB] = 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.
. 2026 Feb 2.
doi: 10.1021/acs.jmedchem.5c03704. Online ahead of print.
Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease
Qiangqiang Wei[SUP] 1 [/SUP], Ashley J Taylor[SUP] 1 [/SUP], Nagaraju Miriyala[SUP] 1 [/SUP], Mahesh A Barmade[SUP] 1 [/SUP], Zachary O Gentry[SUP] 1 [/SUP], Jordan Anderson-Daniels[SUP] 2 [/SUP], Kevin B Teuscher[SUP] 1 [/SUP], Mackenzie M Crow[SUP] 1 [/SUP], Chideraa Apakama[SUP] 1 [/SUP], Taylor M South[SUP] 1 [/SUP], Tyson A Rietz[SUP] 1 [/SUP], Kangsa Amporndanai[SUP] 1 [/SUP], Jason Phan[SUP] 1 [/SUP], John L Sensintaffar[SUP] 1 [/SUP], Mark Denison[SUP] 2 [/SUP], Taekyu Lee[SUP] 1 [/SUP], Stephen W Fesik[SUP] 1 3 4 [/SUP]
Affiliations
- PMID: 41629155
- DOI: 10.1021/acs.jmedchem.5c03704
The papain-like protease (PL[SUP]Pro[/SUP]) 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[SUP]Pro[/SUP] 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[SUP]Pro[/SUP] inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC[SUB]50[/SUB] = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC[SUB]50[/SUB] = 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.