High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites

Abstract Antimalarial drug resistance compels the quest for new compounds that target alternative pathways to current drugs. The Plasmodium cyclic GMP-dependent protein kinase (PKG) has essential functions in all of the major life cycle developmental stages. An imidazopyridine PKG inhibitor scaffold...

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Autores principales:	Maria Penzo, Laura de las Heras-Dueña, Lydia Mata-Cantero, Beatriz Diaz-Hernandez, Maria-Jesus Vazquez-Muñiz, Sonja Ghidelli-Disse, Gerard Drewes, Elena Fernandez-Alvaro, David A. Baker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b1853796974419994e20d37569169f5
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spelling	oai:doaj.org-article:7b1853796974419994e20d37569169f52021-12-02T16:07:54ZHigh-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites10.1038/s41598-019-42801-x2045-2322https://doaj.org/article/7b1853796974419994e20d37569169f52019-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-42801-xhttps://doaj.org/toc/2045-2322Abstract Antimalarial drug resistance compels the quest for new compounds that target alternative pathways to current drugs. The Plasmodium cyclic GMP-dependent protein kinase (PKG) has essential functions in all of the major life cycle developmental stages. An imidazopyridine PKG inhibitor scaffold was previously shown to clear P. falciparum infection in a rodent model in vivo and blocked transmission to mosquitoes providing proof of concept for this target. To find new classes of PKG inhibitors to serve as alternative chemical starting points, we performed a high-throughput screen of the GSK Full Diversity Collection using recombinant P. falciparum PKG. We developed a robust enzymatic assay in a 1536-well plate format. Promising compounds were then tested for activity against P. falciparum asexual blood stage growth, selectivity and cytotoxicity. By using a scoring system we selected the 66 most promising PKG inhibitors (comprising nine clusters and seven singletons). Among these, thiazoles were the most potent scaffold with mid-nanomolar activity on P. falciparum blood stage and gamete development. Using Kinobeads profiling we identified additional P. falciparum protein kinases targeted by the thiazoles that mediate a faster speed of the kill than PKG-selective compounds. This scaffold represents a promising starting point to develop a new antimalarial.Maria PenzoLaura de las Heras-DueñaLydia Mata-CanteroBeatriz Diaz-HernandezMaria-Jesus Vazquez-MuñizSonja Ghidelli-DisseGerard DrewesElena Fernandez-AlvaroDavid A. BakerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Penzo Laura de las Heras-Dueña Lydia Mata-Cantero Beatriz Diaz-Hernandez Maria-Jesus Vazquez-Muñiz Sonja Ghidelli-Disse Gerard Drewes Elena Fernandez-Alvaro David A. Baker High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
description	Abstract Antimalarial drug resistance compels the quest for new compounds that target alternative pathways to current drugs. The Plasmodium cyclic GMP-dependent protein kinase (PKG) has essential functions in all of the major life cycle developmental stages. An imidazopyridine PKG inhibitor scaffold was previously shown to clear P. falciparum infection in a rodent model in vivo and blocked transmission to mosquitoes providing proof of concept for this target. To find new classes of PKG inhibitors to serve as alternative chemical starting points, we performed a high-throughput screen of the GSK Full Diversity Collection using recombinant P. falciparum PKG. We developed a robust enzymatic assay in a 1536-well plate format. Promising compounds were then tested for activity against P. falciparum asexual blood stage growth, selectivity and cytotoxicity. By using a scoring system we selected the 66 most promising PKG inhibitors (comprising nine clusters and seven singletons). Among these, thiazoles were the most potent scaffold with mid-nanomolar activity on P. falciparum blood stage and gamete development. Using Kinobeads profiling we identified additional P. falciparum protein kinases targeted by the thiazoles that mediate a faster speed of the kill than PKG-selective compounds. This scaffold represents a promising starting point to develop a new antimalarial.
format	article
author	Maria Penzo Laura de las Heras-Dueña Lydia Mata-Cantero Beatriz Diaz-Hernandez Maria-Jesus Vazquez-Muñiz Sonja Ghidelli-Disse Gerard Drewes Elena Fernandez-Alvaro David A. Baker
author_facet	Maria Penzo Laura de las Heras-Dueña Lydia Mata-Cantero Beatriz Diaz-Hernandez Maria-Jesus Vazquez-Muñiz Sonja Ghidelli-Disse Gerard Drewes Elena Fernandez-Alvaro David A. Baker
author_sort	Maria Penzo
title	High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
title_short	High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
title_full	High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
title_fullStr	High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
title_full_unstemmed	High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
title_sort	high-throughput screening of the plasmodium falciparum cgmp-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/7b1853796974419994e20d37569169f5
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High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites

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