R01AI150610

Lead Optimization of Hepatitis B Virus Ribonuclease H Inhibitors - Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >250 million people worldwide and kills ~870,000 annually.

Therapy primarily employs nucleos(t)ide analog drugs against viral DNA synthesis that often drive viremia below the detection limit. However, replication is not eliminated, and HBV resurges if drugs are withdrawn. Nevertheless, treatment cures up to 6% of patients, so more patients could be cured by suppressing HBV further.

Reverse transcription requires the viral ribonuclease H (RNaseH) that destroys the RNA after it has been copied into DNA. Blocking the RNaseH prevents synthesis of viral genomes, including both the key nuclear cccDNA form of the genome and the DNA in virions. Drugs have not yet been designed against the RNaseH.

We developed the first screening pipeline for HBV RNaseH inhibitors and found >150 inhibitors that block HBV replication. The most effective is an N-hydroxypyridinedione (HPD) with an EC50 of 0.11 μM and a therapeutic index (TI, CC50/EC50) of 300. An HPD hit compound suppressed HBV viremia in mice with humanized livers.

We also found that napthyridinones [NPTH, comprised of true napthyridinones (HNOS) and the closely related hydroxypyridopyrimidinones (HPPS)] inhibit HBV replication with EC50s as low as 0.95 μM and TIs up to 83. Achieving EC50s as low as 0.11 μM and TIs up to 350 after assessing only 51 HPDs, combined with good activity of the related NPTH chemotype, led Drs. Tavis (HBV virologist), Meyers, Zhan, and Zoidis and (medicinal chemists) to join forces to develop the HPDs and NPTHs into pre-clinical leads for novel HBV drugs.

Aim 1. Lead optimization of HPD HBV inhibitors. We will synthesize up to 125 HPDs based on our existing structure-activity relationships (SAR) and evaluate their efficacy, cytotoxicity, and solubility.

Aim 2. Hit-to-lead development of NPTH HBV inhibitors. We will synthesize up to 100 HNOS and 100 HPPS and evaluate their efficacy, cytotoxicity, and solubility.

Aim 3. Assess specificity for HBV of the novel inhibitors. We will evaluate HPDs and NPTHs for induction of heteroduplex formation in HBV capsids and suppression of cccDNA formation. Synergy with other HBV drugs will be assessed. Selectivity will be measured against microbial pathogens and human metalloenzymes including RNaseH1.

Aim 4. Evaluate pharmacological parameters for HPD and NPTH HBV inhibitors. We will assess stability, cellular permeability, plasma protein binding, pharmacokinetics, and toxicology of key inhibitors. Efficacy of the best compounds will be tested against HBV replication in HBV-infected mice carrying humanized livers.

These studies will advance HBV RNaseH inhibitors as first-in-mechanism and first-in-class HBV drug leads. The eventual anti-HBV RNaseH drugs are anticipated to be used in combination with nucleos(t)ide analogs to suppress HBV replication enough to clear HBV in many more patients than current therapies achieve.

Saint Louis 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]

Missouri United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 397% from $654,955 to $3,253,243.