R01AI173229

Anti-norovirus protease inhibitors for immunocompromised patients - project summary/abstract

Human noroviruses (HNoV), which belong to the Caliciviridae family, are the leading cause of viral gastroenteritis and food-borne disease worldwide. Each year in the United States alone, HNoV is responsible for greater than 21 million cases of acute gastroenteritis, leading to an estimated 71,000 hospitalizations per year. While most cases resolve within a week, immunocompromised patients, children, and the elderly have an elevated risk of long-term and even fatal infections.

Currently, there are no antiviral drugs or vaccines approved for the prevention or treatment of chronic HNoV infections. The main goal of this project is to harness the medical benefits that are offered by the inhibition of viral enzymes, including the HNoV protease. The overall objective of this proposal is to design and develop a protease inhibitor for the treatment of HNoV infections.

The HNoV NS6 protease has become an attractive drug target due to its essential role in the viral replication cycle. The central hypothesis is that small-molecule inhibitors targeting the viral protease will limit or eliminate HNoV infections. The rationale for the proposed research is based on our preliminary data, specifically Compound 1 and its analogs. These compounds are unique, non-toxic, small peptidomimetic molecules that inhibit HNoV replication selectively in culture at 20 nM EC50 by interacting with the HNoV protease.

Pharmacological manipulation of the HNoV protease is expected to result in new and innovative approaches to the prevention and treatment of HNoV infections. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims:

Aim 1) To optimize and discover and develop broad-spectrum oral HNoV PIs by multiparameter optimization and molecular modeling approaches of lead compounds from our proprietary library.

Aim 2) To perform mechanism of action (MOA) and resistance studies of the lead HNoV PIs.

Aim 3) To evaluate the lead HNoV PIs in an immunocompromised mouse model.

Under the first aim, about 25 compounds will be designed, synthesized, and tested per year. Under the second aim, enzyme kinetic, crystallographic, host protease inhibition, inhibition of HNoV protease production, and drug resistance studies will be performed with the lead compounds. Under the third aim, anti-HNoV efficacy studies will be performed in an immunodeficient mouse model.

This approach is innovative because we developed a research plan taking full advantage of five recent advances: (1) producing HNoV PR recombinant proteins in milligram amounts; (2) solving the crystal structure of the HNoV GII.4 PR - the main drug target; (3) a cell-based HNoV replicon assay; (4) 3D human intestinal enteroid model, and (5) an immunocompromised mouse disease model to study human HNoV infection.

The proposed research is significant because in-depth pre-clinical studies and characterization of these new peptidomimetics could lead to the approval of the first safe and effective drugs for the treatment of chronic HNoV infections, which cause significant morbidity and mortality in immunocompromised patients.

Emory 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]

Atlanta, Georgia 303221119 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 285% from $796,178 to $3,063,131.