R01AI193216

DEVELOPING INHIBITORS OF SEASONAL AND PANDEMIC INFLUENZA VIRUSES - SUMMARY INFLUENZA VIRUSES ARE A LEADING CAUSE OF HUMAN DISEASE DUE TO RESPIRATORY VIRAL INFECTION WORLDWIDE. IT IS THE OVERARCHING OBJECTIVE OF THIS PROJECT TO ADVANCE PRODRUG CONJUGATES OF 4’-FLUOROURIDINE (4’-FLU), A NOVEL PYRIMIDINE ANALOG WITH CONFIRMED BROAD ORAL EFFICACY AGAINST INFLUENZA VIRUSES, AND AT LEAST ONE NON-NUCLEOSIDE INHIBITOR OF THE INFLUENZA VIRUS POLYMERASE COMPLEX, TO THE STAGE OF FORMAL PRECLINICAL DEVELOPMENT AND ASSEMBLY OF AN INVESTIGATIONAL NEW DRUG-ENABLING PACKAGE. THE PROJECT DESIGN IS DRIVEN BY OUR UNDERLYING HYPOTHESIS THAT EFFECTIVE NEXT-GENERATION THERAPEUTICS FOR THE TREATMENT OF INFLUENZA MUST BE ORALLY AVAILABLE, DISPLAY A BROAD INDICATION SPECTRUM AGAINST INFLUENZA VIRUS ISOLATES OF HUMAN, AVIAN, AND SWINE LINEAGES, AND IDEALLY COVER BOTH INFLUENZA A (IAV) AND B (IBV) VIRUSES. THESE PRODUCT PROFILE DEMANDS ARE DERIVED FROM THE CLINICAL BURDEN IMPOSED BY THE DIVERSE SPECTRUM OF SEASONAL INFLUENZA VIRUSES, THE PANDEMIC POTENTIAL ARISING FROM SPILLOVER OF ZOONOTIC AVIAN VIRUSES INTO THE HUMAN POPULATION, AND CURRENT FDA RECOMMENDATIONS THAT RECOGNIZE OUTPATIENT ADULTS SUFFERING FROM SEASONAL INFLUENZA AS THE PRIMARY PATIENT POPULATION FOR INITIAL CLINICAL TESTING. THESE DEVELOPMENTAL OBJECTIVES ARE BEST MET WITH DIRECT ACTING THERAPEUTICS, SINCE HOST-TARGETED ANTIVIRAL THERAPIES, ALTHOUGH OFTEN TANTALIZINGLY BROAD IN INDICATION RANGE, ARE PRONE TO UNACCEPTABLE SIDE EFFECTS THAT ARE INCOMPATIBLE WITH THE PRIMARY PATIENT GROUP PURSUED. IN PREVIOUS WORK UNDERPINNING THIS PROGRAM, WE HAVE DEMONSTRATED BROAD-SPECTRUM ANTIVIRAL ACTIVITY OF 4’-FLU IN CULTURED CELLS AND ANIMAL INFECTION MODELS AGAINST A CLINICALLY SIGNIFICANT PANEL OF RNA VIRUSES. AGAINST THE INFLUENZA VIRUS INDICATION, 4’-FLU HAS CONFIRMED ORAL EFFICACY AGAINST SEASONAL, PANDEMIC, AND HIGHLY PATHOGENIC AVIAN INFLUENZA VIRUSES IN RODENT AND NON-RODENT MODELS. THE COMPOUND TRIGGERS IMMEDIATE CHAIN TERMINATION OF THE INFLUENZA VIRUS RNA-DEPENDENT RNA POLYMERASE (RDRP) COMPLEX AND CARRIES A HIGH BARRIER TO VIRAL RESISTANCE. IN PREPARATION OF CLINICAL DEVELOPMENT, WE HAVE GENERATED PRODRUG CONJUGATES OF 4’-FLU TO OPTIMIZE DELIVERY ACROSS THE GASTROINTESTINAL EPITHELIUM. TO BROADEN OUR INFLUENZA VIRUS RDRP INHIBITOR PORTFOLIO, WE HAVE IDENTIFIED A SET OF NON-NUCLEOSIDE RDRP INHIBITORS IN A LARGE-SCALE HIGH-THROUGHPUT SCREENING CAMPAIGN THAT WILL BE ADVANCED SIMULTANEOUSLY AS COMPANION DRUGS OR FOR COMBINATION THERAPY IN A MULTI- PRONGED APPROACH. TO SELECT A CLINICAL CANDIDATE FOR FORMAL DEVELOPMENT, 4’-FLU PRODRUG CONJUGATES WILL BE SUBJECTED TO DE-RISKING EFFICACY AND TOLERABILITY TESTING IN RELEVANT RODENT AND NON-RODENT ANIMAL MODELS AND DOSING PARADIGMS EXPLORED THROUGH INTERFACING OF DYNAMIC PK PROFILES WITH PERFORMANCE IN HUMAN AIRWAY EPITHELIUM ORGANOIDS (AIM 1). NON-NUCLEOSIDE RDRP INHIBITOR LEAD CANDIDATE SCAFFOLDS WILL BE SYNTHETICALLY DEVELOPED, MECHANISTICALLY CHARACTERIZED, AND SUBJECTED TO PROOF-OF-CONCEPT EFFICACY TESTING (AIM 2). EMERGING NON-NUCLEOSIDE LEADS WILL BE QUERIED FOR COMBINATION THERAPY WITH THE 4’-FLU CLINICAL CANDIDATE AND THE EFFECT OF MONO- AND COMBINATION THERAPY ON SUPPRESSING INFLUENZA VIRUS TRANSMISSION DETERMINED IN FERRETS (AIM 3).

Georgia State University Research Foundation

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]

Georgia United States

State-Wide

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