Plasmodium Dihydroorotate Dehydrogenase: A Promising Target for Novel Anti-Malarial Chemotherapy

Abstract

Malaria remains a globally prevalent infectious disease that leads to significant morbidity and mortality. While there are a number of drugs approved for its treatment, drug resistance has compromised most of them, making the development of new drugs for the treatment and prevention of malaria essential. The completion of the Plasmodium falciparum genome and a growing understanding of parasite biology are fueling the search for novel drug targets. Despite this, few targets have been chemically validated in vivo. The pyrimidine biosynthetic pathway illustrates one of the best examples of successful identification of anti-malarial drug targets. This review focuses on recent studies to exploit the fourth enzyme in the de novo pyrimidine biosynthetic pathway of P. falciparum, dihydroorotate dehydrogenase (PfDHODH), as a new target for drug discovery. Several chemical scaffolds have been identified by high throughput screening as potent inhibitors of PfDHODH and these show strong selectivity for the malarial enzyme over that from the human host. Potent activity against parasites in whole cell models with good correlation between activity on the enzyme and the parasite have also been observed for a number of the identified series. Lead optimization of a triazolopyrimidine-based series has identified an analog with prolonged plasma exposure, that is orally bioavailable, and which shows good efficacy against the in vivo mouse model of the disease. These data provide strong evidence that PfDHODH is a validated target for the identification of new antimalarial chemotherapy. The challenge remains to identify compounds with the necessary combination of potency and metabolic stability to allow identification of a clinical candidate. KeywordsMalaria; Plasmodium; pyrimidine biosynthesis; dihydroorotate dehydrogenase; drug discovery Malaria the disease, and the current state of chemotherapyMalaria is a global disease caused by protozoan Apicomplexan parasites of the Plasmodium species and is transmitted by the Anopheles mosquito [1,2]. It is endemic in 90 countries, putting over 2 billion people at risk and leading to the deaths of 1-2 million people annually. Pregnant woman and children are the most susceptible to severe disease. Until the early 1950s malaria was endemic in parts of the US and Europe, but it was eliminated through extensive control programs. It is now found primarily in tropical and subtropical countries with the African population most at risk. A number of anti-malarial agents are in clinical use, however the development of resistance to both chloroquine and sulfadoxine-pyrimethamine led to the * Author to whom all correspondence should be addressed. margaret.phillips@UTSouthwestern.edu; Tel: (214) 645-6164. NIH Public Access Author ManuscriptInfect Disord Drug Targets. Author manuscript; available in PMC 2010 June 10. Published in final edited form as:Infect Disord Drug Targets. 2010 June ; 10(3): 226-239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript rapid increase in the...

Current therapies and future possibilities for drug development against liver-stage malaria

“…However, this approach requires the knowledge of a validated or well-characterized molecular target. For example, the recent efforts to develop the first Plasmodium DHODH inhibitor led to the rational design and clinical development of a novel compound with liver-and blood-stage activity, DSM265 (55,56).…”

Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

“…Many of the clinically relevant anti-malarial agents that have a known mechanism of action directly or indirectly affect pyrimidine metabolism. Drugs targeting dihydrofolate reductase (DHFR) or dihydropteroate synthetase (e.g., pyrimethamine, cycloguanil, sulphonamides and sulphones) disrupt folate metabolism, which is essential for the formation of thymidine 9 . Also the lactate dehydrogenase enzyme of P. falciparum has the ability to rapidly use 3-acetyl pyridine NAD as a coenzyme in the reaction leading to the formation of pyruvate from lactate 10 .…”

Development of a Novel High-Density [ 3 H]Hypoxanthine Scintillation Proximity Assay To Assess Plasmodium falciparum Growth

“…In the last few decades, very few P. falciparum targets with low sequence similarity or even no sequence similarity to known human orthologues, to avoid selectivity issues, have been demonstrated to be essential for the parasite (20)(21)(22). Even when many molecules with the capacity to modify the activity of these targets have been discovered using biochemical assays, hits have had a limited success due to the lack of whole-cell activity (23).…”