R01AI153100

Fosinopril Analogs for the Treatment of Human Babesiosis

Babesiosis is a malaria-like illness found worldwide and endemic in the United States. The disease is caused by intraerythrocytic parasites of the genus Babesia. Babesia microti and Babesia duncani, which are responsible for most cases reported in the United States, are transmitted to humans by Ixodes scapularis and Dermacentor albipictus ticks, respectively, and can also be introduced by blood transfusion.

The current treatment for human babesiosis consists of combination therapies with atovaquone+azithromycin or clindamycin+quinine. However, these drugs are associated with a high rate of recrudescence, treatment failures, and adverse events. Furthermore, recent studies in mice infected with B. microti and in vitro with B. duncani showed that these parasites are naturally tolerant to these drugs. These limitations emphasize the need for more effective and safer therapies for the treatment of human babesiosis.

We have recently reported the development of a continuous in vitro culture system for B. duncani in human red blood cells. Using this assay, we screened a library of FDA-approved drugs and identified fosinopril (the prodrug of the dipeptidyl carboxypeptidase ACE inhibitor fosinoprilat) as a potent antibabesial inhibitor. The compound was also effective against both B. duncani and B. microti in mouse models of babesiosis at 10 mg/kg. Interestingly, neither fosinoprilat nor other ACE inhibitors affected the growth of B. duncani in vitro. Equally interesting, analysis of the structure of fosinopril and bortezomib (another potent inhibitor of B. duncani identified in the chemical screen and a known proteasome inhibitor) revealed similarities between the two compounds. Together, these data suggest that the antibabesial activity of fosinopril could be due to inhibition of either an ACE-like peptidase and/or a proteasome activity of Babesia parasites.

The primary goals of this application are to identify analogs of fosinopril with more potent antibabesial but no ACE activity, and to elucidate the mechanism of action of these compounds in Babesia parasites. Building upon our preliminary data, we propose the following three specific aims.

In Aim 1, we will determine whether or not the prodrug form of fosinopril is the active compound, and characterize the efficacy of fosinopril and newly synthesized analogs against B. duncani and B. microti clinical and field isolates in vitro and examine the structure-activity relationship specific to these parasites.

In Aim 2, we will characterize the in vivo efficacy of the most active compounds alone or in combination with other drugs as a strategy for the elimination of Babesia infections.

In Aim 3, we will implement biochemical, mass spectrometry, and genetic assays to elucidate the mode of action of and possible mechanisms of Babesia resistance to fosinopril and its analogs.

The success of the proposed three aims will guide future clinical trials to create an ideal regimen for the treatment of human babesiosis with no recrudescence.

Yale Univ

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]

New Haven, Connecticut 065191612 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 391% from $742,773 to $3,646,365.