Structure-based design of SARS-CoV-2 papain-like protease inhibitors

Prakash Jadhav; Bo Huang; Jerzy Osipiuk; Xiaoming Zhang; Haozhou Tan; Christine Tesar; Michael Endres; Robert Jedrzejczak; Bin Tan; Xufang Deng; Andrzej Joachimiak; Jianfeng Cai; Jun Wang

doi:10.1016/j.ejmech.2023.116011

Structure-based design of SARS-CoV-2 papain-like protease inhibitors

Prakash Jadhav, Bo Huang, Jerzy Osipiuk, Xiaoming Zhang, Haozhou Tan, Christine Tesar, Michael Endres, Robert Jedrzejczak, Bin Tan, Xufang Deng, Andrzej Joachimiak, Jianfeng Cai, Jun Wang

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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^pro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PL^pro cleaves at three sites of the viral polyproteins. In addition, PL^pro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PL^pro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PL^pro) 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^pro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.

Original language	English (US)
Article number	116011
Journal	European journal of medicinal chemistry
Volume	264
DOIs	https://doi.org/10.1016/j.ejmech.2023.116011
State	Published - Jan 15 2024
Externally published	Yes

Keywords

Antiviral
Coronavirus
PL
Papain-like protease
SARS-CoV-2

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2023.116011

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title = "Structure-based design of SARS-CoV-2 papain-like protease inhibitors",

abstract = "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.",

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author = "Prakash Jadhav and Bo Huang and Jerzy Osipiuk and Xiaoming Zhang and Haozhou Tan and Christine Tesar and Michael Endres and Robert Jedrzejczak and Bin Tan and Xufang Deng and Andrzej Joachimiak and Jianfeng Cai and Jun Wang",

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doi = "10.1016/j.ejmech.2023.116011",

language = "English (US)",

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T1 - Structure-based design of SARS-CoV-2 papain-like protease inhibitors

AU - Jadhav, Prakash

AU - Huang, Bo

AU - Osipiuk, Jerzy

AU - Zhang, Xiaoming

AU - Tan, Haozhou

AU - Tesar, Christine

AU - Endres, Michael

AU - Jedrzejczak, Robert

AU - Tan, Bin

AU - Deng, Xufang

AU - Joachimiak, Andrzej

AU - Cai, Jianfeng

AU - Wang, Jun

PY - 2024/1/15

Y1 - 2024/1/15

N2 - 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.

AB - 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.

KW - Antiviral

KW - Coronavirus

KW - PL

KW - Papain-like protease

KW - SARS-CoV-2

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Structure-based design of SARS-CoV-2 papain-like protease inhibitors

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Keywords

ASJC Scopus subject areas

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