Abstract
Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the pathogen of the Coronavirus disease-19 (COVID-19), is still devastating the world causing significant chaos to the international community and posing a significant threat to global health. Since the first outbreak in late 2019, several lines of intervention have been developed to prevent the spread of this virus. Nowadays, some vaccines have been approved and extensively administered. However, the fact that SARS-CoV-2 rapidly mutates makes the efficacy and safety of this approach constantly under debate. Therefore, antivirals are still needed to combat the infection of SARS-CoV-2. Papain-like protease (PLpro) of SARS-CoV-2 supports viral reproduction and suppresses the innate immune response of the host, which makes PLpro an attractive pharmaceutical target. Inhibition of PLpro could not only prevent viral replication but also restore the antiviral immunity of the host, resulting in the speedy recovery of the patient. In this review, we describe structural and functional features on PLpro of SARS-CoV-2 and the latest development in searching for PLpro inhibitors. Currently available inhibitors targeting PLpro as well as their structural basis are also summarized.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) (Wu F. et al, 2020; Zhu et al, 2020), is the third highly pathogenic human coronavirus in this century after the SARS-CoV emerged in 2003 (Stadler et al, 2003) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 (Chafekar and Fielding, 2018)
Papain-like protease (PLpro), a multifunctional protease of SARS-CoV-2, can digest the polyprotein precursor to generate non-structural proteins and mitigate the RIG-I-mediated innate immunity triggered by viral infection (Klemm et al, 2020; Shin et al, 2020)
This review updates the research progress in developing novel and potent inhibitors of SARS-CoV2 PLpro, which may reveal some insights into future drug discovery and new strategies for the COVID-19 combat
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) (Wu F. et al, 2020; Zhu et al, 2020), is the third highly pathogenic human coronavirus in this century after the SARS-CoV emerged in 2003 (Stadler et al, 2003) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 (Chafekar and Fielding, 2018). As not all the identified lead compounds exhibited desired activities, co-crystallization of these effective inhibitors with PLpro is often adopted to investigate how the two molecules interact (Wang et al, 2021), which can inform further lead optimization and future drug design.
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