<i>Trichomonas vaginalis</i> 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 since 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. 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 (UNH). The guanosine analog, ribavirin, however, was identified as a unique inhibitor of GACNH with an IC50 value of 8.6 μM. IC50 values for ribavirin against AGNH and UNH could not be determined as complete inhibition was not observed at the highest concentrations tested. However, the % inhibition at 250 μM was determined to be 83% and 58% for AGNH and UNH, respectively. Since GACNH also catalyzes the hydrolysis of cytidine, the amino group of ribavirin could also be forming similar interactions in the active site as the cytosine base. This might explain ribavirin’s lack of UNH inhibition, with the UNH active site being optimized for the uracil ring containing a carbonyl group in place of the cytosine amino group. Ribavirin provides a chemical starting point for the design of more potent GACNH-selective inhibitors.

Ribavirin selectively inhibits the guanosine/adenosine/cytidine nucleoside hydrolase from <i>Trichomonas vaginalis</i>

255th National Meeting (2018)

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Ribavirin selectively inhibits the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis