# Proteasome inhibitors against mucosal protozoan pathogens

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $648,435

## Abstract

Project Summary
 Trichomonas vaginalis is the causative agent of trichomoniasis, the most common, non-viral sexually-
transmitted disease, with 5-7 million cases in the U.S. and >200 million in the world each year. In addition to
infections of the urogenital tract, trichomoniasis increases the risk of adverse pregnancy outcomes, HIV
transmission, and cervical and prostate cancer. Only two drugs of the same class are FDA-approved for
treatment, the nitro drugs metronidazole and tinidazole. Although generally effective, treatment failures occur in
a substantial fraction of patients and the drugs have significant liabilities, with moderate to severe adverse
effects and poor compliance due to seemingly benign but common side effects such as metallic taste. Given its
prevalence, its association with multiple disease outcomes, and an increase in nitro drug-resistant strains, new
antimicrobials against T. vaginalis are urgently needed, particularly in women where infection can persist for
months or even years compared to generally less than ten days in men. In extensive preliminary studies, we
determined that inhibitors of the proteasome, an essential cellular machinery for the degradation and recycling
of cell proteins, kill T. vaginalis at sub-micromolar levels. Importantly, the inhibitors overcome nitro drug
resistance and are efficacious in a murine model of trichomonad infection. We have also isolated and
biochemically characterized proteasomes from T. vaginalis and human HeLa cells and found that they display
significant differences in their peptide substrate specificity, providing the rationale for designing new potent and
parasite-selective proteasome inhibitors. Based on these promising findings, the project has the overall
objective to develop novel proteasome inhibitors with greatly improved potency and selectivity for the treatment
of trichomoniasis. Using a hit compound with 50-fold selectivity, we will systematically develop T. vaginalis-
specific proteasome inhibitors using a comprehensive combination of medicinal chemistry efforts, functional
testing with multiple clinical strains of T. vaginalis, biochemical and structural investigations of the parasite
proteasomes, and efficacy and toxicity testing in murine infection models. We have assembled a superb team
of investigators with complementary expertise in parasitology, protease biology, antimicrobial drug
development, and medicinal and peptide chemistry. The team has the experience and track record to conduct
the critical pre-clinical studies to establish proteasome inhibitors as a new class of agents in the therapeutic
armamentarium against trichomoniasis.

## Key facts

- **NIH application ID:** 10367246
- **Project number:** 1R01AI158612-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** LARS ECKMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $648,435
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367246

## Citation

> US National Institutes of Health, RePORTER application 10367246, Proteasome inhibitors against mucosal protozoan pathogens (1R01AI158612-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10367246. Licensed CC0.

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