Structural Basis for Inhibition of the SARS-CoV-2 nsp16 by Substrate-Based Dual Site Inhibitors
ChemMedChem 2024
Gints Kalniņš, Laura Ruduša, Anna L. Bula, Diāna Zeļencova-Gopejenko, Olga Bobiļeva, Mihails Sisovs, Kaspars Tārs, Aigars Jirgensons, Kristaps Jaudzems, Raitis Bobrovs

Coronaviruses, including SARS-CoV-2, possess an mRNA 5′ capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2′-O- of subsequent nucleotides of viral mRNA. The 2′-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.


Atslēgas vārdi
Medicinal chemistry | Methyltransferase | nsp16 | SARS-CoV-2 | Structural biology
DOI
10.1002/cmdc.202400618
Hipersaite
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202400618

Kalniņš, G., Ruduša, L., Bula, A., Zeļencova-Gopejenko, D., Bobiļeva, O., Sisovs, M., Tārs, K., Jirgensons, A., Jaudzems, K., Bobrovs, R. Structural Basis for Inhibition of the SARS-CoV-2 nsp16 by Substrate-Based Dual Site Inhibitors. ChemMedChem, 2024, Vol. 19, No. 24, Article number e202400618. ISSN 1860-7179. e-ISSN 1860-7187. Pieejams: doi:10.1002/cmdc.202400618

Publikācijas valoda
English (en)
RTU Zinātniskā bibliotēka.
E-pasts: uzzinas@rtu.lv; Tālr: +371 28399196