The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

Otava, Tomáš; Šála, Michal; Li, F.; Fanfrlík, Jindřich; Devkota, K.; Perveen, S.; Chau, I.; Pakarian, P.; Hobza, Pavel; Vedadi, M.; Bouřa, Evžen; Nencka, Radim

doi:https://dx.doi.org/10.1021/acsinfecdis.1c00131

Počet záznamů: 1

The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

1.

SYSNO ASEP	0544555
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors
Tvůrce(i)	Otava, Tomáš (UOCHB-X)_ORCID Šála, Michal (UOCHB-X)_{RID, ORCID} Li, F. (CA) Fanfrlík, Jindřich (UOCHB-X)_{RID, ORCID} Devkota, K. (CA) Perveen, S. (CA) Chau, I. (CA) Pakarian, P. (CA) Hobza, Pavel (UOCHB-X)_{RID, ORCID} Vedadi, M. (CA) Bouřa, Evžen (UOCHB-X)_ORCID Nencka, Radim (UOCHB-X)_{RID, ORCID}
Zdroj.dok.	ACS Infectious Diseases. - : American Chemical Society - ISSN 2373-8227 Roč. 7, č. 8 (2021), s. 2214-2220
Poč.str.	7 s.
Jazyk dok.	eng - angličtina
Země vyd.	US - Spojené státy americké
Klíč. slova	COVID-19 ; SARS-CoV-2 ; methyltransferase ; nsp14 nsp10 ; structure-based design ; inhibitors
Obor OECD	Microbiology
CEP	EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
	NU20-05-00472 GA MZd - Ministerstvo zdravotnictví
Způsob publikování	Omezený přístup
Institucionální podpora	UOCHB-X - RVO:61388963
UT WOS	000685949500021
EID SCOPUS	85110951126
DOI	10.1021/acsinfecdis.1c00131
Anotace	In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes the transfer of the methyl group from S-adenosyl-l-methionine (SAM) to cap the guanosine triphosphate moiety of the newly synthesized viral RNA, yielding the methylated capped RNA and S-adenosyl-l-homocysteine (SAH). As the crystal structure of SARS-CoV-2 nsp14 is unknown, we have taken advantage of its high homology to SARS-CoV nsp14 and prepared its homology model, which has allowed us to identify novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target. We have synthesized and tested the designed compounds in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme. The docking studies nicely explain the contribution of an aromatic part attached by a linker to the position 7 of the 7-deaza analogues of SAH.
Pracoviště	Ústav organické chemie a biochemie
Kontakt	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418
Rok sběru	2022
Elektronická adresa	https://doi.org/10.1021/acsinfecdis.1c00131

Počet záznamů: 1