A Comparative Assessment Study of Known Small-molecule GPVI Modulators.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
10 Feb 2022
10 Feb 2022
Historique:
received:
29
07
2021
accepted:
10
12
2021
entrez:
18
2
2022
pubmed:
19
2
2022
medline:
19
2
2022
Statut:
epublish
Résumé
The GPVI platelet receptor was recently validated as a safe antiplatelet target for the treatment of thrombosis using several peptidic modulators. In contrast, few weakly potent small-molecule GPVI antagonists have been reported. Those that have been published often lack evidence for target engagement, and their biological efficacy cannot be compared because of the natural donor variability associated with the assays implemented. Herein, we present the first side-by-side assessment of the reported GPVI small-molecule modulators. We have characterized their functional activities on platelet activation and aggregation using flow cytometry as well as light transmission and electrical impedance aggregometry. We also utilized microscale thermophoresis (MST) and saturation transfer difference (STD) NMR to validate GPVI binding and have used this along with molecular modeling to suggest potential binding interactions. We conclude that of the compounds examined, losartan and compound
Identifiants
pubmed: 35178172
doi: 10.1021/acsmedchemlett.1c00414
pmc: PMC8842102
doi:
Types de publication
Journal Article
Langues
eng
Pagination
171-181Subventions
Organisme : British Heart Foundation
ID : FS/17/66/33480
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/16/6/31941
Pays : United Kingdom
Informations de copyright
© 2022 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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