# Engineering protease-resistant antiviral peptide inhibitors for SARS-CoV-2

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $722,958

## Abstract

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 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 β-
amino acid residues generates α/β-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-
CoV2 and MERS live viruses in vitro, blocks spread of SARS-CoV2 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-CoV2 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 α/β-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 α/β-lipopeptide fusion inhibitors against
SARS-CoV-2 infection in hamsters. Analysis of in vivo biodistribution and toxicity of backbone modified S-
CoV-2 α/β-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.

## Key facts

- **NIH application ID:** 10457971
- **Project number:** 5R01AI160961-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Anne Moscona
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $722,958
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457971

## Citation

> US National Institutes of Health, RePORTER application 10457971, Engineering protease-resistant antiviral peptide inhibitors for SARS-CoV-2 (5R01AI160961-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10457971. Licensed CC0.

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