Journal Article

DKFZ-2026-01121

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Inhibitors Targeting SARS-CoV-2 Papain-Like Protease: Screening, Design, Synthesis, and Biological Evaluation.

Iuga, E.-O. ; Gone, N. ; de Godoy, M. O. ; Verissimo, G. C. ; de Jesus Agostinetto, G. ; Urich, L. ; Krüger, N. ; Kronenberger, T. ; Guido, R. V. C. ; O'Donoghue, A. J. ; Laufer, S. A.DKFZ* ; Pillaiyar, T.

2026
Wiley-VCH Weinheim

Abstract: Despite the availability of vaccines and antiviral drugs, SARS-CoV-2 still presents a global health threat, emphasizing the need for new therapeutic targets beyond the main protease and RNA-dependent RNA polymerase. The papain-like protease (PLpro) is a highly conserved and essential viral enzyme that drives polyprotein processing and suppresses host innate immune responses through its deubiquitinating and deISGylating activities. This study employed two approaches to identify new PLpro inhibitors: (i) the design and synthesis of a range of non-covalent PLpro inhibitors based on a lead compound, GRL0617. (ii) Screening the in-house library for new covalent PLpro inhibitors. Biochemical assays demonstrated effective inhibition of PLpro activity, particularly with the non-covalent inhibitor 2t (TPG-2t, IC50 = 0.634 µM) and with potential covalent inhibitors such as 13e (IC50 = 22.0 µM) and 13f (TPG-13f, IC50 = 5.0 µM). 2t exhibited antiviral activity (EC50 = 2.89 µM) without causing cellular toxicity. Molecular modeling suggests that 2t can establish stable binding interactions within the PLpro active site. Therefore, inhibitor 2t could be a promising candidate for future antiviral development.

Keyword(s): SARS-CoV-2: enzymology (MeSH) ; SARS-CoV-2: drug effects (MeSH) ; Antiviral Agents: pharmacology (MeSH) ; Antiviral Agents: chemical synthesis (MeSH) ; Antiviral Agents: chemistry (MeSH) ; Drug Design (MeSH) ; Humans (MeSH) ; Coronavirus Papain-Like Proteases: antagonists & inhibitors (MeSH) ; Coronavirus Papain-Like Proteases: metabolism (MeSH) ; Structure-Activity Relationship (MeSH) ; Protease Inhibitors: pharmacology (MeSH) ; Protease Inhibitors: chemical synthesis (MeSH) ; Protease Inhibitors: chemistry (MeSH) ; COVID-19 Drug Treatment (MeSH) ; Molecular Docking Simulation (MeSH) ; Drug Evaluation, Preclinical (MeSH) ; COVID‐19 ; SARS‐CoV‐2 ; antiviral ; non‐covalent inhibitors ; papain‐like protease ; Antiviral Agents ; Coronavirus Papain-Like Proteases ; papain-like protease, SARS-CoV-2 ; Protease Inhibitors

Note: #NCTZFB9#

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Contributing Institute(s):

1. Koordinierungsstelle NCT SüdWest (SW01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF < 5 ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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