First-in-class inhibitors of Nsp15 endoribonuclease of SARS-CoV-2: modeling, synthesis, and enzymatic assay of thiazolidinedione and rhodanine analogs

Nimer Mehyar; Nosaibah Samman; Shatha Al Gheribi; Abdullah Mashhour; Pearl Chan; Rabih O Al-Kaysi; Stanley Perlman; Mohamed Boudjelal; Imadul Islam

doi:10.1016/j.jbc.2025.110409

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First-in-class inhibitors of Nsp15 endoribonuclease of SARS-CoV-2: modeling, synthesis, and enzymatic assay of thiazolidinedione and rhodanine analogs

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First-in-class inhibitors of Nsp15 endoribonuclease of SARS-CoV-2: modeling, synthesis, and enzymatic assay of thiazolidinedione and rhodanine analogs

Nimer Mehyar, Nosaibah Samman, Shatha Al Gheribi, Abdullah Mashhour, Pearl Chan, Rabih O Al-Kaysi, Stanley Perlman, Mohamed Boudjelal and Imadul Islam

The Journal of biological chemistry, Vol.301(8), 110409

08/2025

DOI: 10.1016/j.jbc.2025.110409

PMCID: PMC12303054

PMID: 40562099

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Abstract

During infection, the coronavirus Nsp15, a uridine-specific endoribonuclease, suppresses the host cell's antiviral response. Recently, researchers have paid more attention to this relatively underexplored yet potentially viable drug target. In this study, we employed fluorescence resonance energy transfer-based screening assays to identify potent Nsp15 inhibitors. Subsequently, we used active-site in silico docking methods to design new molecules with enhanced inhibitory properties. Solution assays were used to measure the potency and determine the mechanism of these inhibitors. We identified a novel class of thiazolidinedione and rhodanine analogs that inhibit SARS-CoV-2 Nsp15. Docking these compounds into the uridine-binding site shows that most analogs form two hydrogen bonds with Ser294. The most potent inhibitors are compounds KCO237 and KCO251 (half-maximal inhibitory concentration: 0.304 μM, 0.931 μM respectively). The inhibition kinetics of KCO237 and KCO251 best align with a reversible mixed inhibition model. Mutating Ser294 did not completely abolish Nsp15 activity or the inhibitory effect of KCO237 or KCO251. These findings suggest that thiazolidinedione and rhodanine analogs likely inhibit Nsp15 by binding to the uridine active site while also implicating a possible secondary allosteric binding site. The ability of these compounds to inhibit VERO 6 cell infection with SARS-CoV-2 at subtoxic levels highlights their potential for development as novel antiviral treatments for SARS-CoV-2 and other coronavirus-related diseases.

docking

SARS-CoV-2

endoribonuclease

inhibition mechanism

thiazolidinedione

inhibitor

fluorescence resonance energy transfer

Nsp15

rhodanine

enzyme mutation

Details

Title: Subtitle: First-in-class inhibitors of Nsp15 endoribonuclease of SARS-CoV-2: modeling, synthesis, and enzymatic assay of thiazolidinedione and rhodanine analogs
Creators: Nimer Mehyar - National Guard Health Affairs
Nosaibah Samman - National Guard Health Affairs
Shatha Al Gheribi - National Guard Health Affairs
Abdullah Mashhour - National Guard Health Affairs
Pearl Chan - University of Iowa, Microbiology and Immunology
Rabih O Al-Kaysi - King Abdulaziz Medical City
Stanley Perlman - University of Iowa
Mohamed Boudjelal - National Guard Health Affairs
Imadul Islam - National Guard Health Affairs
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.301(8), 110409
DOI: 10.1016/j.jbc.2025.110409
PMID: 40562099
PMCID: PMC12303054
NLM abbreviation: J Biol Chem
ISSN: 1083-351X
eISSN: 1083-351X
Publisher: ELSEVIER
Grant note: King Abdullah International Medical Research Center, KAIMRC: RC20/219
Funding and additional information-This research work was funded by the King Abdullah International Medical Research Center, KAIMRC (project no.: RC20/219) .
Language: English
Electronic publication date: 06/23/2025
Date published: 08/2025
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9984833633802771

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