tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Dec 5:264:116011.
doi: 10.1016/j.ejmech.2023.116011. Online ahead of print. Structure-based design of SARS-CoV-2 papain-like protease inhibitors
Prakash Jadhav[SUP] 1 [/SUP], Bo Huang[SUP] 2 [/SUP], Jerzy Osipiuk[SUP] 3 [/SUP], Xiaoming Zhang[SUP] 4 [/SUP], Haozhou Tan[SUP] 1 [/SUP], Christine Tesar[SUP] 5 [/SUP], Michael Endres[SUP] 5 [/SUP], Robert Jedrzejczak[SUP] 5 [/SUP], Bin Tan[SUP] 1 [/SUP], Xufang Deng[SUP] 6 [/SUP], Andrzej Joachimiak[SUP] 7 [/SUP], Jianfeng Cai[SUP] 8 [/SUP], Jun Wang[SUP] 9 [/SUP]
Affiliations
The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PL[SUP]pro[/SUP]) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PL[SUP]pro[/SUP] cleaves at three sites of the viral polyproteins. In addition, PL[SUP]pro[/SUP] antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PL[SUP]pro[/SUP] is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PL[SUP]pro[/SUP]) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PL[SUP]pro[/SUP] inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.
Keywords: Antiviral; Coronavirus; PL(pro); Papain-like protease; SARS-CoV-2.
. 2023 Dec 5:264:116011.
doi: 10.1016/j.ejmech.2023.116011. Online ahead of print. Structure-based design of SARS-CoV-2 papain-like protease inhibitors
Prakash Jadhav[SUP] 1 [/SUP], Bo Huang[SUP] 2 [/SUP], Jerzy Osipiuk[SUP] 3 [/SUP], Xiaoming Zhang[SUP] 4 [/SUP], Haozhou Tan[SUP] 1 [/SUP], Christine Tesar[SUP] 5 [/SUP], Michael Endres[SUP] 5 [/SUP], Robert Jedrzejczak[SUP] 5 [/SUP], Bin Tan[SUP] 1 [/SUP], Xufang Deng[SUP] 6 [/SUP], Andrzej Joachimiak[SUP] 7 [/SUP], Jianfeng Cai[SUP] 8 [/SUP], Jun Wang[SUP] 9 [/SUP]
Affiliations
- PMID: 38065031
- DOI: 10.1016/j.ejmech.2023.116011
The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PL[SUP]pro[/SUP]) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PL[SUP]pro[/SUP] cleaves at three sites of the viral polyproteins. In addition, PL[SUP]pro[/SUP] antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PL[SUP]pro[/SUP] is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PL[SUP]pro[/SUP]) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PL[SUP]pro[/SUP] inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.
Keywords: Antiviral; Coronavirus; PL(pro); Papain-like protease; SARS-CoV-2.