Druggability of the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis

Abstract

Trichomonas vaginalis infects approximately 300 million people worldwide annually. Infected individuals have a higher susceptibility to more serious conditions such as cervical and prostate cancer. The parasite has developed increasing resistance to current drug therapies, with an estimated 5% of clinical cases resulting from resistant strains, creating the need for new therapeutic strategies with novel mechanisms of action. Nucleoside salvage pathway enzymes represent novel drug targets as these pathways are essential for the parasite's survival. The guanosine/adenosine/cytidine nucleoside hydrolase (GACNH) may be particularly important as its expression is upregulated under glucose-limiting conditions mimicking those that occur during infection establishment. GACNH was screened against the NIH Clinical Collection to explore its druggability. Seven compounds were identified with IC values <20 μM. Extensive overlap was found between inhibitors of GACNH and the adenosine/guanosine nucleoside hydrolase (AGNH), but no overlap was found with inhibitors of the uridine nucleoside hydrolase. The guanosine analog ribavirin was the only compound found to be specific for GACNH. Compounds that inhibit both AGNH and GACNH purine salvage pathway enzymes may prove critical given the role that GACNH appears to play in the early stages of infection.

Enzymatic Transition States and Drug Design

“…In the IAG-nucleoside hydrolase from Trypanosoma vivax (TvNH), leaving group protonation is implicated. 97 The catalytic site Ca 2+ binding is similar to CfNH, but instead of the weakly interacting groups at the purine/ pyrimidine leaving group site, TvNH has the purine leaving group in a hydrophobic stack with a pair of tryptophan residues, Trp83 and Trp260 (Figures 13 and 14). This interaction is proposed to favor electron donation into the leaving group, raising the p K a to permit protonation by solvent.…”

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

“…21 Moreover, different flavonoids from the subclasses of flavonols and dihydroflavonols have been shown to inhibit two nucleoside hydrolases from the protozoa Trichomonas vaginalis, with IC 50 values ranging from 0.2 to 20 μM. 54,55 Our group recently identified flavonoids capable of inhibiting the LdNH. 23 Polyphenolic substances, such as flavonoids and tannins, are indeed well-known for their ability to interact with protein targets, as is discussed in the following section.…”

Structure, Oligomerization and Activity Modulation in N-Ribohydrolases

“…Although NHs are extremely attractive drug targets due to their absence in mammalian hosts, it remains to be seen whether these enzymes may play a crucial role in the metabolic pathways of other pathogens. Pathogens such as T. vaginalis are both purine and pyrimidine auxotrophic, and the dependence of their life cycle on the genome-encoded NHs could be inferred [ 92 , 93 , 94 ]. The finding that the yeast NH URH1 is active on pyridine nucleosides (such as nicotinamide riboside) links NHs to components of the redox cofactors NAD + and NADPH, and further suggests that the enzyme may have a specialized—yet, so far not fully identified—role in different organisms [ 14 ].…”