Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

Abstract

Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.

Keywords: Antiviral; Aspergillus fumigatus; Babesia bovis; Babesia caballi; Bioisosterism; Brequinar; Dihydroorotate dehydrogenase (DHODH) inhibitors; Helicobacter pilory; Leflunomide; Leishmania; Malaria; Plasmodium falciparum; Plasmodium vivax; Pseudomonas aeruginosa; Schistosoma mansoni; Teriflunomide; Theileria equi; Toxoplasma gondii; Trypanosoma; hDHODH.