In:
Science, American Association for the Advancement of Science (AAAS), Vol. 365, No. 6456 ( 2019-08-30)
Abstract:
The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase Pf CLK3, which we used in combination with chemogenetics to validate Pf CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for Pf CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of Pf CLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi . Hence, our data establish Pf CLK3 as a target for drugs, with the potential to offer a cure—to be prophylactic and transmission blocking in malaria.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.aau1682
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2019
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11