R01AI158612

PROTEASOME INHIBITORS AGAINST MUCOSAL PROTOZOAN PATHOGENS - 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.

San Diego University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

La Jolla, California 920930063 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 400% from $648,435 to $3,242,175.