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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 1 , Bo Huang 2 , Jerzy Osipiuk 3 , Xiaoming Zhang 4 , Haozhou Tan 1 , Christine Tesar 5 , Michael Endres 5 , Robert Jedrzejczak 5 , Bin Tan 1 , Xufang Deng 6 , Andrzej Joachimiak 7 , Jianfeng Cai 8 , Jun Wang 9
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 (PLpro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PLpro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PLpro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PLpro) 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 PLpro 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 1 , Bo Huang 2 , Jerzy Osipiuk 3 , Xiaoming Zhang 4 , Haozhou Tan 1 , Christine Tesar 5 , Michael Endres 5 , Robert Jedrzejczak 5 , Bin Tan 1 , Xufang Deng 6 , Andrzej Joachimiak 7 , Jianfeng Cai 8 , Jun Wang 9
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 (PLpro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PLpro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PLpro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PLpro) 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 PLpro 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.