20S Proteasome as a Drug Target in Trichomonas vaginalis

Abstract

Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven α and seven β subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its >5-fold greater potency against the β1 and β5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.

Marine Cyanobacteria: A Source of Lead Compounds and their Clinically-Relevant Molecular Targets

“…Moreover, the study showed that incorporating a d-amino acid at the P3 position can significantly modulate host cytotoxicity without interfering significantly with anti-plasmodial activity [61]. In another study, a carmaphycin-related synthetic analogue, carmaphycin-17 (18, Figure 3), was found to have greater inhibitory activity against Trichomonas vaginalis than the reference drug metronidazole [62]. Trichomonas vaginalis is the causative agent of the sexually transmitted disease, trichomoniasis.…”

“…Trichomonas vaginalis is the causative agent of the sexually transmitted disease, trichomoniasis. In addition, 18 was found to be selective for T. vaginalis due to its increased potency against the β1 and β5 catalytic subunits of the T. vaginalis proteasome as compared to the human proteasome subunits [62]. Compound 18 is also shown to be selective for the Schistosoma mansoni proteasome (about 13.2fold more potent) over the human proteasome [63].…”

Anti-trichomonad activities of different compounds from foods, marine products, and medicinal plants: a review

“…Will inhibition of the virulence enzyme protect males against trichomoniasis? O'Donoghue, Bibo-Verdugo [16] showed that clinically approved cancer drugs that inhibit the proteasome also have high activity in the enriched T. vaginalis in cell-free assays. The proteasome inhibitor carmaphycin-17 ( Fig.…”

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

“…That said, new therapies are urgently needed given the lack of effective vaccines, drug resistance, limited efficacy, and toxicity associated with current treatment [4][5][6]. Given that the UPS pathway is essential for cell survival, inhibition of the proteasome has emerged as an attractive anti-parasitic target [7][8][9][10][11][12][13]. However, the regulation of UPS-mediated protein degradation in clinically important protozoans remains poorly understood.…”