Metabolic enzymes of helminth parasites: potential as drug targets

Abstract

Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

The Mechanism of Action of Praziquantel: Can New Drugs Exploit Similar Mechanisms?

“…This compound has some activity against S. mansoni, although it is not as effective as PZQ [179,180]. Therefore, a renewed focus on studying and targeting metabolic enzymes and processes in schistosomes may also be a worthwhile strategy [181]. While the identification of novel targets provides the greatest scope for the discovery of new anti-schsitosomal drugs, the variety and diversity of possibly targets is considerable.…”

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

“…Although the pp-GalNAc family members are likely to be similar in structure and catalytic mechanism, there are examples of drugs which differentiate between highly similar enzymes. For example, sildenafil (Viagra) selectively inhibits one human phosphodiesterase isoform and Clorsulon inhibits highly conserved glycolytic enzymes yet selects for helminth parasite enzymes over the mammalian host enzymes [75,76].…”

Schistosoma mansoni does not and cannot oxidise fatty acids, but these are used for biosynthetic purposes instead

“…Thereafter fatty acid β-oxidation has acquired a lot of attention and most general reports on schistosomiasis now state that fatty acid oxidation is essential for egg production in female schistosomes (Colley et al, 2014;Guigas and Molofsky, 2015;Oliveira et al, 2016;Pearce and Huang, 2015). Subsequently, the postulated fatty acid β-oxidation process was subject of studies on gene expression in schistosomes (Buro et al, 2013;Li et al, 2017) and of studies that aimed to identify novel drugs for schistosomiasis (Edwards et al, 2015;Timson, 2016) However, the assumption that fatty acid oxidation occurs in schistosomes is still controversial as fatty acid oxidation has never been demonstrated directly in S. mansoni, nor in any other parasitic trematode for that matter (Frayha and Smyth, 1983;Rumjanek and Simpson, 1980;Saz, 1981). This has prompted us to perform a comprehensive analysis of the lipid metabolism of S. mansoni.…”