9HH6

Crystal Structure of Nsp15 Endoribonuclease from SARS CoV-2 in Complex with TAS-103

This is a non-PDB format compatible entry.

Summary for 9HH6

• Entry DOI: 10.2210/pdb9hh6/pdb
• Descriptor: ORF1ab polyprotein, 6-[2-(dimethylamino)ethylamino]-3-oxidanyl-indeno[2,1-c]quinolin-7-one, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: uridylate-specific endoribonuclease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 78975.62

Authors

Chatziefthymiou, S.D.,Kolbe, M.,Hakanpaeae, J.,Labahn, J.,Windshuegel, B. (deposition date: 2024-11-21, release date: 2025-05-28)

Primary citation

Chatziefthymiou, S.D.,Kuzikov, M.,Afandi, S.,Kovacs, G.,Srivastava, S.,Zaliani, A.,Gruzinov, A.,Pompidor, G.,Lunelli, M.,Ahmed, G.R.,Labahn, J.,Hakanpaa, J.,Windshugel, B.,Kolbe, M.
Identification, validation, and characterization of approved and investigational drugs interfering with the SARS-CoV-2 endoribonuclease Nsp15.
Protein Sci., 34:e70156-e70156, 2025

PubMed 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 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.

PubMed: 40371758
DOI: 10.1002/pro.70156

Experimental method

SOLUTION SCATTERING
X-RAY DIFFRACTION (2 Å)