Dihydroorotate Dehydrogenase Inhibitors in Antimalarial Drug Discovery

Dihydroorotate dehydrogenase (DHODH) catalyses a key step in the de novo biosynthesis of pyrimidines, an essential pathway for Plasmodium parasites that cannot salvage these nucleotides from the host. Inhibitors of plasmodial DHODH exploit structural differences in the parasite enzyme to achieve high selectivity over the human orthologue, blocking DNA and RNA synthesis and arresting parasite growth in both liver and blood stages. Medicinal chemistry campaigns have yielded several chemical series—triazolopyrimidines, benzamidylthiophenes and sulfonylureas among them—exhibiting nanomolar potency and favourable pharmacokinetic properties. The archetypal compound DSM265 demonstrated prolonged plasma half-life and single-dose activity against Plasmodium falciparum, motivating its clinical evaluation. Resistance selection studies have revealed point mutations and copy-number changes in the DHODH binding site, underscoring the need for combination regimens and diversified scaffolds. Advances in structural biology have illuminated binding-mode plasticity, enabling rational design of next-generation inhibitors with reduced propensity for cross-resistance. By targeting an obligate metabolic enzyme with conserved essentiality across Plasmodium species, DHODH inhibitors represent a promising pillar in the antimalarial portfolio, with the potential to contribute both therapeutic and prophylactic solutions in support of eradication efforts.

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Technical terms

Dihydroorotate Dehydrogenase (DHODH): A mitochondrial enzyme in Plasmodium that catalyses oxidation of dihydroorotate to orotate in pyrimidine biosynthesis.

De novo Pyrimidine Biosynthesis: The metabolic pathway by which organisms synthesise pyrimidine nucleotides from basic precursors rather than salvaging them.

IC₅₀: The concentration of an inhibitor required to reduce enzyme or parasite growth activity by 50 per cent in vitro.

Species Selectivity: The ratio of inhibitor potency against the parasite enzyme versus the human enzyme, reflecting therapeutic window.

Resistance Mutation: A genetic alteration in the target enzyme that reduces inhibitor binding or efficacy, potentially leading to treatment failure.

References

1. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study. The Lancet Infectious Diseases (2018).
2. In Vitro Resistance Selections for Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors Give Mutants with Multiple Point Mutations in the Drug-binding Site and Altered Growth*. Journal of Biological Chemistry (2014).
3. Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds*. Journal of Biological Chemistry (2009).
4. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*. Journal of Biological Chemistry (2010).
5. High-throughput Screening for Potent and Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase*. Journal of Biological Chemistry (2005).