Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum

Abstract

Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.

Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

“…Many of the enzymes involved in Plasmodium nucleic acid biosynthesis differ from those of their human hosts. Accordingly, nucleic acid biosynthesis pathways have long been considered exploitable targets for novel antimalarial drug design (43)(44)(45)(46). For example, P. falciparum bifunctional dihydrofolate reductase-thymidylate synthase mediates the conversion of dihydrofolic acid (dihydrofolate; vitamin B9) to tetrahydrofolic acid by dihydrofolate (44).…”

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

“…Atovaquone-proguanil, which is primarily used for presumptive treatment during short-term visits to countries where malaria is endemic, inhibits the cytochrome bc 1 complex (19)(20)(21). Interestingly, the antimalarial activity of atovaquone-proguanil strictly depends on arrest of the pyrimidine biosynthesis pathway by indirect inhibition of Plasmodium dihydroorotate dehydrogenase, which relies on the ETC to recycle electrons (17,22). On the other hand, the respiratory activity of the Plasmodium ETC is essential during parasite development in the Anopheles vector, as shown by normal blood stage growth and complete arrest of oocyst development in Plasmodium berghei mutants that contain targeted deletions of type II NADH:ubiquinone dehydrogenase or the ATP synthase ␤ subunit (23,24).…”

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

“…The orotic acid is so turned into orotidine 5′-monophosphate (OMP) by addition to 5′-phospo-D-ribosyl-α-1-pyrophosphate, a step carried out by orotate phosphoribosyltransferase (OPRT). OMP is subsequently decarboxylated to uridine 5′-monophosphate (UMP), the precursor of all other pyrimidine nucleotides and deoxynucleotides needed for nucleic acid synthesis [159]. Excepting for PfDHODH, which is discussed in the ETC topic, the enzymes involved in de novo pyrimidine biosynthesis pathway that could potentially be exploited for the discovery of novel antimalarials as discussed below.…”

“…This enzyme catalyzes the reversible cyclization of N-carbamoyl-l-aspartate (CA-asp) to l-dihydroorotate (L-DHO) [159]. Orotate and a series of 5-substituted derivatives were found to inhibit competitively the purified enzyme from P. falciparum culture.…”