R01AI160052

De Novo Design of Minibinder Antagonists for COVID-19 and Future Pandemics - Project Summary

One of the most pressing public health priorities for the COVID-19 pandemic is the development of an effective and inexpensive therapeutic. The long-term goal of this proposal is to develop such COVID-19 treatments, as well as the methods needed to rapidly create such molecules as soon as any new pathogen is identified.

The central hypothesis is that computational design can be used to quickly create proteins with potent antiviral activity and others that suppress "cytokine storms" associated with advanced infection. Such countermeasures, if rapidly developed and deployed, could save millions of lives during an outbreak until vaccines are developed.

The specific aims are to:

1) Overcome current limitations in the discovery and development of protein therapeutics by creating methods for the de novo design of hyper-stable miniproteins that bind tightly to vulnerable binding sites on the SARS-CoV-2 spike glycoprotein, including the receptor binding domain (RBD) of the ACE-2 cellular receptor and the fusion peptide region.

2) Enhance the avidity of such anti-spike minibinders through genetic fusion of multiple copies, or through rational design of higher-order oligomers to create drug compounds that are less prone to viral mutagenic escape.

3) Apply the same minibinder design pipeline to create cytokine receptor antagonists of key cytokines IL-6 and IL-1β likely involved in acute respiratory distress syndrome (ARDS) associated with COVID-19 mortality.

4) Assess the efficacy of antiviral and anti-interleukin minibinders by several routes of delivery (intravenous, intranasal, and subcutaneous) in rodent models of COVID-19 and assess immunogenicity in order to identify those designs best suited for further preclinical development.

As proof of principle, the first anti-spike minibinders have already been designed, were found to bind to SARS-CoV-2 spike RBD, and were found to neutralize live virus with activities rivaling the most potent known antibodies.

This proposal is innovative because it seeks to apply powerful emerging methods in the computational design of new protein therapeutics to the COVID-19 pandemic. The proposal is significant because it would be the first example of computational protein design yielding potent and entirely de novo antiviral and anti-inflammatory therapeutics for an active pandemic.

Ultimately, rapid minibinder design methods have the potential to generate treatments for future pandemics, as well as for many other common and neglected diseases and conditions.

University Of Washington

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]

Seattle, Washington 981951016 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 384% from $723,634 to $3,504,899.