Dataset Information

Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.

ABSTRACT: Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC(50) < 1 nM) and toxicity to cultured parasites at low concentrations (ED(50) < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.

SUBMITTER: Glenn MP

PROVIDER: S-EPMC2728208 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.

Glenn Matthew P MP Chang Sung-Youn SY Hornéy Carrie C Rivas Kasey K Yokoyama Kohei K Pusateri Erin E EE Fletcher Steven S Cummings Christopher G CG Buckner Frederick S FS Pendyala Prakash R PR Chakrabarti Debopam D Sebti Saïd M SM Gelb Michael M Van Voorhis Wesley C WC Hamilton Andrew D AD

Journal of medicinal chemistry 20060901 19

Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold se ...[more]

PMID: 16970397

Similar Datasets

Project description:Control of malaria is threatened by emerging parasite resistance to artemisinin drug (ART) therapies. The molecular details of how Plasmodium malaria parasites response to ART and how this relates to resistance is not clear. To determine how parasites respond to ART by altering gene expression, we performed a transcriptomic study of dihydroartemisinin (DHA) response in P. falciparum K1 strain and in P. berghei ANKA strain. Microarray data from DHA-treated P. falciparum trophozoite stage parasites were compared with data from other ART treatments. Genes with consistent changes in expression were identified, which includes notably down-regulation of cytosolic ribosomal protein genes. RNA-seq data revealed a similar pattern of transcriptomic change, although the pattern was much clearer in that more than one-third of P. falciparum trophozoite genes are differentially expressed with greater statistical support for down-regulation of ribosomal protein genes. The poor overlap of differentially-expressed genes between microarray and RNA-seq and less-well defined patterns for the former suggests that the accuracy of microarray is limited by technological bias. The trophozoite response to DHA is overall “ring-like” and less “trophozoite-like”, which is consistent with previous findings that Plasmodium can enter a quiescent ring-like state to resist ART. RNA-seq data from DHA-treated P. falciparum rings reveal a more muted response, although there is considerable overlap of differentially expressed genes with DHA-treated trophozoites. In contrast, P. falciparum schizonts are unresponsive to DHA, suggesting that the protective response acts mainly to arrest parasite development through the G2/M checkpoint. The transcriptional response of P. berghei to DHA treatment in vivo in infected mice is strikingly similar to the P. falciparum in vitro ring and trophozoite responses, in which ribosomal protein genes are notably down-regulated. These results suggest Plasmodium species respond to DHA in the same way. This knowledge could be applied to outwit the parasite to deliver more effective artemisinin therapies, and maybe hinder the development of drug resistance.

Dataset Information

Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.

Publications

Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets