R01AI161973

Discovery and Optimization of Antifungal Acetyl CoA Synthetase Inhibitors - Project Summary

Recently, we discovered that a small molecule inhibitor of acetyl CoA synthetase (ACS), AR-12, has broad spectrum fungicidal activity in vitro and promising activity in vivo. Consistent with this broad spectrum of activity, genetic studies indicate that ACS is essential for viability in multiple fungi (C. albicans, Fusarium, S. cerevisiae). In contrast, ACS is not essential in mammals. This is likely because, in mammals and plants, the vast majority of acetyl CoA is derived from ATP-citrate lyase (ACL) and not ACS. The most important exception to this rule is the cancer cell where ACS is the predominant source of acetyl CoA. Consequently, ACS has emerged as an anti-cancer target. Although the development of AR-12 stalled, we propose that its target, ACS, remains worthy of further exploration as the basis for a new class of antifungal drugs.

To identify novel inhibitors of fungal ACS, we have developed a multi-disciplinary approach based on:

1) Two complementary small molecule screening strategies;
2) The structural characterization of ACS-inhibitor complexes from multiple pathogenic fungi;
3) Whole cell assays of ACS function and inhibition; and
4) Medicinal chemistry strategies that have already yielded micromolar inhibitors of ACS.

An STD-NMR screen with C. neoformans ACS1 identified 492 ACS interacting molecular fragments, of which the vast majority also interacted with multiple fungal ACS enzymes. In Aim 1, we will further characterize these hits. As a parallel strategy, we adapted our ACS activity assay for high throughput screening (HTS) with the goal of directly identifying small molecule ACS inhibitors.

Our chemistry plan (Aim 2) is guided, in part, by the hypothesis that molecules mimicking the acetyl adenosine-monophosphate ester (ACAMP) intermediate are likely to be effective inhibitors. In Aim 2A, we will characterize the acetyl-PO3 binding pocket by a structure-activity study of ACAMP mimics derived from molecules already crystallized in the active site of fungal ACS. Biochemically stable, potent acetyl-PO3 isosteres emerging from this analysis will then be linked with putative ATP/AMP-binding pocket-targeted fragments to assemble candidate non-nucleoside, bi-substrate ACS inhibitors. To complement this hypothesis-based strategy, candidate inhibitors will also be assembled from other strongly interacting fragments, and we will optimize inhibitors directly identified in the ACS activity-based HTS screen (Aims 2B&C).

New molecules will be evaluated (Aim 3) with a testing funnel that includes biochemical characterization of ACS inhibition, antifungal activity against a range of pathogenic fungi, whole cell assays of on-target activity against ACS, and initial in vitro toxicity/ADME characterization. Our goal is to identify a lead ACS inhibitor scaffold along with a back-up series for further pre-clinical development as broad-spectrum antifungal drug candidates.

The University Of Iowa

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]

Iowa City, Iowa 52242 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 407% from $599,458 to $3,039,162.