R01AI164473

Optimizing CDPK1 Inhibitors for Chronic Toxoplasmosis - Project Summary

Toxoplasma gondii is an opportunistic pathogen that causes disease in immunocompromised patients and in infants due to congenital infections. Following a brief acute phase, the parasite differentiates into a semi-dormant form called the bradyzoite, which resides within long-lived tissue cysts primarily located in the central nervous system (CNS).

Despite a vigorous immune response, tissue cysts are not eliminated and pose a risk of reactivation when immunity wanes. It is estimated that approximately 2 billion people worldwide are chronically infected with T. gondii and therefore at risk of reactivation should their immune function decline. In many regions of South America, infection can lead to severe and recurrent ocular disease in immunocompetent individuals.

Chemotherapy is available for acute toxoplasmosis based on a combination of pyrimethamine and sulfadiazine. However, there are complications due to the toxicity of pyrimethamine and allergic reactions to sulfa drugs. Moreover, this treatment poses risks during pregnancy due to teratogenicity. Current treatment is effective in controlling acute infection but has minimal effect on chronic tissue cyst stages and therefore is not curative.

Although a number of new compounds have been shown to inhibit T. gondii growth in vitro, most have little effect on the chronic stage. Hence, there is a major need for new efforts to identify compounds for treating chronic toxoplasmosis.

The goal of this project is to identify late-stage preclinical leads that show potent inhibition of parasite growth in vitro, eliminate chronic infection in vivo, and possess appropriate ADME (absorption, distribution, metabolism, and excretion) and safety profiles for advancement. We will develop potent and selective inhibitors of TGCDPK1, which is a unique and essential enzyme in T. gondii. In preliminary studies, we have identified several lead compounds that are both highly potent and selective for TGCDPK1 over mammalian kinases.

We will design and synthesize new analogs to improve potency, selectivity, CNS penetration, bioavailability, and ADMET-PK (absorption, distribution, metabolism, excretion, and pharmacokinetics) properties of these compounds. Specific criteria for potency, selectivity, and ADMET properties will be used to advance compounds to in vivo testing.

We have developed new quantitative assays for monitoring inhibition of acute and chronic stages of infection, and we will employ animal models for monitoring the efficacy of compounds against reactivated toxoplasmosis in the CNS.

Successful achievement of these milestones will deliver lead compound(s) for future IND-enabling studies with the eventual goal of curing chronic toxoplasmosis.

Washington University

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]

Saint Louis, Missouri 631101010 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 297% from $787,253 to $3,122,353.