Journal Article

PUBDB-2025-02032

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identification, validation, and characterization of approved and investigational drugs interfering with the SARS ‐ CoV ‐2 endoribonuclease Nsp15

Chatziefthymiou, S. D. ; Kuzikov, M. ; Afandi, S. ; Kovacs, G. ; Srivastava, S. ; Zaliani, A. ; Gruzinov, A. ; Pompidor, G. ; Lunelli, M. ; Ahmed, G. R. ; Labahn, J. (Corresponding author) ; Hakanpää, J. (Corresponding author) ; Windshügel, B. (Corresponding author) ; Kolbe, M. (Corresponding author)CSSB*

2025
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/pro.70156  doi:10.3204/PUBDB-2025-02032

Abstract: Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3′-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose–response assays confirmed 29 compounds with an IC$_{50}$ below 10 μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

Note: This research was funded by the DESY Strategic Fund (DSF) and by the Horizon Europe Framework Programme (grant agreement number 101137192, AVI-THRAPID).

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Contributing Institute(s):

1. CSSB-HZI-MK (CSSB-HZI-MK)
2. CSSB-CF-SPC (CSSB-CF-SPC)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)
2. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2025

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

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