| Full text | |
| Author(s): Show less - |
Johannsen, Sandra
;
Gierse, Robin M.
;
Kru''ger, Arne
;
Edwards, Rachel L.
;
Nanna, Vittoria
;
Fontana, Anna
;
Zhu, Di
;
Masini, Tiziana
;
de Carvalho, Lais Pessanha
;
Poizat, Mael
;
Kieftenbelt, Bart
;
Hodge, Dana M.
;
Alvarez, Sophie
;
Bunt, Daan
;
Lacour, Antoine
;
Shams, Atanaz
;
Meissner, Kamila Anna
;
de Souza, Edmarcia Elisa
;
Dro''ge, Melloney
;
van Vliet, Bernard
;
den Hartog, Jack
;
Hutter, Michael C.
;
Held, Jana
;
Odom John, Audrey R.
;
Wrenger, Carsten
;
Hirsch, Anna K. H.
Total Authors: 26
|
| Document type: | Journal article |
| Source: | ACS INFECTIOUS DISEASES; v. 10, n. 3, p. 23-pg., 2024-02-17. |
| Abstract | |
In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure-activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated. (AU) | |
| FAPESP's process: | 18/08820-0 - Nanoparticle-assisted drug delivery of Vitamin B6 pathway inhibitors in malaria |
| Grantee: | Arne Kruger |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 15/26722-8 - Drug discovery against human infectious diseases |
| Grantee: | Carsten Wrenger |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 17/03966-4 - Targeting lipoic acid salvage and biosynthesis pathways in MRSA |
| Grantee: | Carsten Wrenger |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 16/24790-9 - Dissecting Plasmodium falciparum EXP1/GST2 for xenobiotic defence in glucose-6-phosphate dehydrogenase deficiency |
| Grantee: | Kamila Anna Meissner |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 20/12277-0 - Drug discovery against human infectious diseases |
| Grantee: | Edmarcia Elisa de Souza |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |