TY  - JOUR
AU  - Chatziefthymiou, Spyros D.
AU  - Kuzikov, Maria
AU  - Afandi, Sara
AU  - Kovacs, Greta
AU  - Srivastava, Sukrit
AU  - Zaliani, Andrea
AU  - Gruzinov, Andrey
AU  - Pompidor, Guillaume
AU  - Lunelli, Michele
AU  - Ahmed, Golam Rizvee
AU  - Labahn, Jörg
AU  - Hakanpää, Johanna
AU  - Windshügel, Björn
AU  - Kolbe, Michael
TI  - Identification, validation, and characterization of approved and investigational drugs interfering with the SARS ‐ CoV ‐2 endoribonuclease Nsp15
JO  - Protein science
VL  - 34
IS  - 6
SN  - 0961-8368
CY  - Hoboken, NJ
PB  - Wiley
M1  - FZJ-2025-03034
SP  - e70156
PY  - 2025
AB  - 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 IC50 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.
LB  - PUB:(DE-HGF)16
C6  - 40371758
UR  - <Go to ISI:>//WOS:001488651400001
DO  - DOI:10.1002/pro.70156
UR  - https://juser.fz-juelich.de/record/1044127
ER  -