Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.
Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC(50) values from 30 nM to 1.6 micrOM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.
Chiang
Annette N
AN
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Valderramos
Juan-Carlos
JC
Balachandran
Raghavan
R
Chovatiya
Raj J
RJ
Mead
Brian P
BP
Schneider
Corinne
C
Bell
Samantha L
SL
Klein
Michael G
MG
Huryn
Donna M
DM
Chen
Xiaojiang S
XS
Day
Billy W
BW
Fidock
David A
DA
Wipf
Peter
P
Brodsky
Jeffrey L
JL
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*
D000577:Amides; D000962:Antimalarials; D018840:HSP70 Heat-Shock Proteins; D011744:Pyrimidinones; D000251:Adenosine Triphosphatases