Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.
Date Issued
2022-11-10
Date Acceptance
2022-09-30
Citation
ACS Medicinal Chemistry Letters, 2022, 13 (11), pp.1715-1722
ISSN
1948-5875
Publisher
American Chemical Society
Start Page
1715
End Page
1722
Journal / Book Title
ACS Medicinal Chemistry Letters
Volume
13
Issue
11
Copyright Statement
© 2022 The Authors. Published by American Chemical Society. This article is available open access under a CC-BY Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/)
License URL
Sponsor
Medical Research Council
Grant Number
MR/N019113/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
kinase domain
drug discovery
inhibitor
Schistosoma
schistosomiasis
crystal structure
docking
inhibition of autophosphorylation
GENITAL SCHISTOSOMIASIS
PRAZIQUANTEL
HIV
0304 Medicinal and Biomolecular Chemistry
0305 Organic Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2022-11-05