Design of inhibitors of SARS-CoV-2 papain-like protease deriving from GRL0617: Structure-activity relationships.

Design of inhibitors of SARS-CoV-2 papain-like protease deriving from GRL0617: Structure-activity relationships.

Publication date: Nov 01, 2024

The unique and complex structure of papain-like protease (PL) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PL may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern. This review article provides a comprehensive overview of PL inhibitors, focusing on the structural framework of the known inhibitor GRL0617 and its analogs. We categorize PL inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70 site, and Cys111 containing catalytic site. We summarize and evaluate the majority of GRL0617-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to GRL0617, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the GRL0617 scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PL, biochemical processes linked to the severe progression of COVID-19. Finally, we summarize the development efforts for SARS-CoV-2 PL inhibitors, in detailed structure-activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PL of current and emerging coronavirus threats.

Concepts Keywords
Advantageous Antiviral Agents
Antiviral Antiviral Agents
Benzylmethylnaphthylethanamines Coronavirus 3C Proteases
Coronavirus Coronavirus 3C Proteases
Val70 Coronavirus Papain-Like Proteases
Coronavirus Papain-Like Proteases
COVID-19
COVID-19 Drug Treatment
Cysteine Proteinase Inhibitors
Cysteine Proteinase Inhibitors
Drug Design
GRL0617-like inhibitors
Humans
papain-like protease, SARS-CoV-2
Protease Inhibitors
Protease Inhibitors
SARS-CoV-2
SARS-CoV-2 coronavirus
Structure-Activity Relationship
Structure–activity relationships

Semantics

Type Source Name
drug DRUGBANK Papain
disease MESH COVID-19
disease MESH cytokine storm
disease MESH respiratory infections
disease IDO site
pathway REACTOME Deubiquitination

Original Article

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