Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum. Author summaryThe Apicomplexa phylum comprises thousands of parasitic species, among which the causative agents of malaria, toxoplasmosis and cryptosporidiosis. New parasiticidal compounds and drugs are urgently needed for treatment of these devastating diseases. As these parasites have adapted innovative pathways for nutrient acquisition, several studies have investigated vitamins and cofactor synthesis and salvage, with the aim of identifying unexplored drug targets. Coenzyme A (CoA) is an essential cofactor for cell biology and is synthesized from pantothenate (Pan, vitamin B5). The discovery of the druggability of CoA synthesis in Plasmodium falciparum has sparked intensive research toward lead compounds identification and preclinical development. Here, we review the current literature on the topic from biological and pharmacological perspectives. Focusing on Plasmodium species and Toxoplasma gondii, we describe recent findings on the importance of Pan synthesis, salvage, and metabolization to CoA in this phylum. In addition, we summarize recent promising advances in the exploration and exploitation of these pathways for lead compounds optimization and drug development.