R01AI160961

Engineering Protease-Resistant Antiviral Peptide Inhibitors for SARS-CoV-2

No vaccines or treatments for SARS-CoV-2 are yet available. A simple prophylactic antiviral strategy would protect naïve individuals from infection now. In the future, when vaccines should be available, a prophylactic antiviral will be essential for individuals who do not mount a suitable immune response.

Antivirals that target viral entry into the host cell have been proven effective against a wide range of viral diseases. The entry/fusion process for CoV (including SARS-CoV-2) is mediated by the viral envelope glycoprotein(s). Concerted action by the receptor-binding domain and the fusion domain is required for fusion. Upon viral attachment (and uptake in certain cases), large-scale conformational rearrangements occur in the fusion domain, driven by the formation of a structure that couples protein refolding directly to membrane fusion.

The formation of this structure can be targeted by fusion inhibitory peptides (C-terminal heptad repeat or HRC peptides) that prevent proper apposition of the HRC and HRN domains in S. We have found that conjugation of a lipid to an inhibitory peptide directs the peptide to cell membranes and increases antiviral efficacy. Analogous lipo-peptides prevent infection by several viruses (measles, Nipah, parainfluenza, influenza) and can be administered via the airway. Treatment is effective for some of these even several days after infection.

In addition, we have shown that modifying the backbone of an HRC peptide via periodic replacement of α-amino acid residues with α,α-disulfide (SS)-amino acid residues generates A/SS-peptides that retain antiviral potency (toward HIV or parainfluenza) but are highly resistant to proteolysis. We recently generated an HRC lipopeptide that is effective against both SARS-CoV-2 and MERS live viruses in vitro, blocks spread of SARS-CoV-2 in human airway tissue, and inhibits transmission of SARS-CoV-2 between ferrets in direct contact.

Here, we propose to combine the lipid conjugation and backbone-modification strategies to generate potent inhibitors of SARS-CoV-2 infection that display a long half-life in vivo.

1. Optimize the antiviral potency and bioavailability of SARS-CoV-2 HRC peptide fusion inhibitors via rational molecular engineering. Antiviral efficacy of A/SS-lipopeptide candidates will be measured in quantitative in vitro assays, in authentic virus infection, and in a human airway model.

2. Evaluate the protection afforded by new backbone-modified A/SS-lipopeptide fusion inhibitors against SARS-CoV-2 infection in hamsters. Analysis of in vivo biodistribution and toxicity of backbone-modified SARS-CoV-2 A/SS-lipopeptide fusion inhibitors and assessment of in vivo potency and resistance mechanisms will lay the foundation for a safe and effective SARS-CoV-2 fusion inhibitor for coronavirus prevention and therapy.

The Trustees Of Columbia University In The City Of New York

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]

New York, New York 100323723 United States

Single Zip Code

Emergency Awards: Rapid Investigation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) (R01 Clinical Trial Not Allowed) (PAR-20-178)

COVID-19 $1,441,650 (40%) percent of this Project Grant was funded by COVID-19 emergency acts including the American Rescue Plan Act of 2021 and the 2020 Coronavirus Preparedness and Response Supplemental Appropriations Act.
Amendment Since initial award the total obligations have increased 366% from $773,390 to $3,600,612.