Journal
ACS OMEGA
Volume 7, Issue 51, Pages 48416-48426Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.2c06675
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Funding
- National Natural Science Foundation of China [82173865, 82130101, 32041005]
- Shenzhen Science and Technology Program [KQTD20170330155106581]
- Major Program of Shenzhen Bay Laboratory [S201101001]
- Shenzhen Bay Laboratory Open Fund [SZBL2021080601010]
- State Key Laboratory of Pathogen and Biosecurity Foundation [SKLPBS1828]
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The PLpro enzyme of SARS-CoV-2 plays a crucial role in virus replication and host immune regulation, making it a potential target for antiviral drugs. In this study, a derivative of chloroxine was found to disrupt the interaction between PLpro and ISG15, showing antiviral effects against SARS-CoV-2 variants.
SARS-CoV-2 has caused a global pandemic of COVID-19, posing a huge threat to public health. The SARS-CoV-2 papain-like cysteine protease (PLpro) plays a significant role in virus replication and host immune regulation, which is a promising antiviral drug target. Several potential inhibitors have been identified in vitro. However, the detailed mechanism of action and structure-activity relationship require further studies. Here, we investigated the structure-activity relationships of the series of derivatives of tanshinone IIA sulfonate sodium (TSS) and chloroxine based on biochemical analysis and molecular dynamics simulation. We found that compound 7, a derivative of chloroxine, can disrupt PLpro-ISG15 interaction and exhibits an antiviral effect for SARS-CoV-2 variants (wild type, delta, and omicron) at the low micromolar level. These studies confirmed that inhibiting PLpro-ISG15 interaction and, thus, restoring the host's innate immunity are effective methods for fighting against viral infection.
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