SARS‐CoV‐2 Papain‐Like Protease: Structure, Function and Inhibition

Ullrich, Sven; Nitsche, Christoph

doi:10.1002/cbic.202200327

Cited by 40 publications

(21 citation statements)

References 100 publications

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“… 313 GRL0617, developed by Ratia et al., was originally used as an inhibitor of SARS‐CoV‐1 PLpro and recently was investigated as an inhibitor of SARS‐CoV‐2 PLpro. 314 A drug‐repurposing screening, carried out using a MedChemExpress bioactive compound library, identified tropifexor as a novel and promising PLpro inhibitor against SARS‐CoV‐2. 315 Recently, through virtual screening of the US FDA‐approved drug library, nine compounds were identified and in vitro biochemical and cell culture‐based studies revealed anti‐SARS‐CoV‐2 PLpro activity of mefloquine and lopinavir.…”

Section: Repurposing Clinically Available Drugs and Therapies For Pat...mentioning

confidence: 99%

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

Xue

Mei

Chen

et al. 2023

MedComm

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The coronavirus disease 2019 (COVID‐19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time‐ and cost‐effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID‐19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID‐19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS‐CoV‐2 variants.

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Section: Repurposing Clinically Available Drugs and Therapies For Pat...mentioning

confidence: 99%

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

Xue

Mei

Chen

et al. 2023

MedComm

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“…SARS-CoV-2 encodes two cysteine proteases—first, the main protease, and then the papain-like protease [ 58 ]. These papain-like proteins have a role in viral replication (such as in the cleavage of viral proteins) and a role in the host immune response [ 58 , 59 ]. Ebselen was identified as a nonspecific cysteine modifier and a main and papain-like protease inhibitor [ 58 , 60 ].…”

Section: Repurposing Of Drugs For Treatment Of Covid-19mentioning

confidence: 99%

An Overview of Repurposed Drugs for Potential COVID-19 Treatment

Govender

Chuturgoon

2022

Antibiotics

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The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.

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“…PL pro is another essential SARS-CoV-2 Cys protease because it cleaves three pro-proteins into their mature forms: Nsp1, Nsp2, and Nsp3 [ 41 ]. The related PL pro from SARS-CoV-1 (causative agent of SARS) has additional roles related to its canonical proteolytic activity, including deubiquitination and deISGylation [ 42 , 43 ], some of which appear to be shared by the 83% identical PL pro from SARS-CoV-2 [ 44 – 46 ].…”

Section: Cysteine Residues In Enzyme Catalysis: Sars-cov-2 Proteasesmentioning

confidence: 99%

Understanding Cysteine Chemistry Using Conventional and Serial X-ray Protein Crystallography

Smith

Wilson

2022

Crystals

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Proteins that use cysteine residues for catalysis or regulation are widely distributed and intensively studied, with many biomedically important examples. Enzymes where cysteine is a catalytic nucleophile typically generate covalent catalytic intermediates whose structures are important for understanding mechanism and for designing targeted inhibitors. The formation of catalytic intermediates can change enzyme conformational dynamics, sometimes activating protein motions that are important for catalytic turnover. However, these transiently populated intermediate species have been challenging to structurally characterize using traditional crystallographic approaches. This review describes the use and promise of new time-resolved serial crystallographic methods to study cysteine-dependent enzymes, with a focus on the main (Mpro) and papain-like (PLpro) cysteine proteases of SARS-CoV-2, as well as on other examples. We review features of cysteine chemistry that are relevant for the design and execution of time-resolved serial crystallography experiments. In addition, we discuss emerging X-ray techniques, such as time-resolved sulfur X-ray spectroscopy, that may be able to detect changes in sulfur charge states and covalency during catalysis or regulatory modification. In summary, cysteine-dependent enzymes have features that make them especially attractive targets for new time-resolved serial crystallography approaches, which can reveal both changes to enzyme structures and dynamics during catalysis in crystalline samples.

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SARS‐CoV‐2 Papain‐Like Protease: Structure, Function and Inhibition

Cited by 40 publications

References 100 publications

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

An Overview of Repurposed Drugs for Potential COVID-19 Treatment

Understanding Cysteine Chemistry Using Conventional and Serial X-ray Protein Crystallography

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