tetano
Editor, Senior Moderator
iScience
. 2022 Oct 2;105254.
doi: 10.1016/j.isci.2022.105254. Online ahead of print.
Chemical screen uncovers novel structural classes of inhibitors of the papain-like protease of coronaviruses
Kwiwan Jeong[SUP] 1 [/SUP], Jinhee Kim[SUP] 2 [/SUP], JuOae Chang[SUP] 3 [/SUP], Subin Hong[SUP] 3 [/SUP], Inseo Kim[SUP] 3 [/SUP], Sunghyun Oh[SUP] 3 [/SUP], Sangeun Jeon[SUP] 2 [/SUP], Joo Chan Lee[SUP] 3 [/SUP], Hyun-Ju Park[SUP] 3 [/SUP], Seungtaek Kim[SUP] 2 [/SUP], Wonsik Lee[SUP] 3 [/SUP]
Affiliations
Abstract
The papain-like protease (PLpro) of coronaviruses is an attractive antiviral target to inhibit both viral replication and interference of the host immune response. We have identified and characterized three novel classes of small molecules, thiophene, cyanofuran, and triazoloquinazoline, as PLpro inhibitors Thiophene inhibited the PLpro of two major coronaviruses, Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) including SARS-CoV-2, while cyanofuran and triazoloquinazoline more selectively inhibited MERS-CoV PLpro. Unlike GRL0617, a known PLpro inhibitor, all three compounds contain no naphthyl group but like GRL0617 were predicted to fit on the cleft near the BL2 loop. Docking studies further revealed that the location and direction of the binding determined their specificity to different coronaviruses. Together, our work demonstrates that the BL2 loop and nearby regions are outstanding druggable targets, and our three inhibitors can be applicable to the development of therapeutics for coronavirus infection.
Keywords: Biochemistry; Computational Biology; MERS-CoV; Microbiology; Molecular Biology; SARS-CoV-2; Subject areas: Virology; coronavirus; papain-like protease; protease inhibitor.
. 2022 Oct 2;105254.
doi: 10.1016/j.isci.2022.105254. Online ahead of print.
Chemical screen uncovers novel structural classes of inhibitors of the papain-like protease of coronaviruses
Kwiwan Jeong[SUP] 1 [/SUP], Jinhee Kim[SUP] 2 [/SUP], JuOae Chang[SUP] 3 [/SUP], Subin Hong[SUP] 3 [/SUP], Inseo Kim[SUP] 3 [/SUP], Sunghyun Oh[SUP] 3 [/SUP], Sangeun Jeon[SUP] 2 [/SUP], Joo Chan Lee[SUP] 3 [/SUP], Hyun-Ju Park[SUP] 3 [/SUP], Seungtaek Kim[SUP] 2 [/SUP], Wonsik Lee[SUP] 3 [/SUP]
Affiliations
- PMID: 36213008
- PMCID: PMC9526870
- DOI: 10.1016/j.isci.2022.105254
Abstract
The papain-like protease (PLpro) of coronaviruses is an attractive antiviral target to inhibit both viral replication and interference of the host immune response. We have identified and characterized three novel classes of small molecules, thiophene, cyanofuran, and triazoloquinazoline, as PLpro inhibitors Thiophene inhibited the PLpro of two major coronaviruses, Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) including SARS-CoV-2, while cyanofuran and triazoloquinazoline more selectively inhibited MERS-CoV PLpro. Unlike GRL0617, a known PLpro inhibitor, all three compounds contain no naphthyl group but like GRL0617 were predicted to fit on the cleft near the BL2 loop. Docking studies further revealed that the location and direction of the binding determined their specificity to different coronaviruses. Together, our work demonstrates that the BL2 loop and nearby regions are outstanding druggable targets, and our three inhibitors can be applicable to the development of therapeutics for coronavirus infection.
Keywords: Biochemistry; Computational Biology; MERS-CoV; Microbiology; Molecular Biology; SARS-CoV-2; Subject areas: Virology; coronavirus; papain-like protease; protease inhibitor.