# Targeting viral envelopes with antiviral peptides and peptoids and degraders, and surface proteins with small molecules

> **NIH NIH U19** · STANFORD UNIVERSITY · 2022 · $2,909,919

## Abstract

ABSTRACT. Our overall objective is to develop a new class of direct acting-antivirals (DAAs) that can specifically
target viral envelopes but not host cell membranes using our novel amphipathic, α-helical (AH) Lipid Envelope
Antiviral Disruption (LEAD) peptides and peptoids (sequence-specific N-substituted glycine oligomers).
Therapeutics that can specifically target enveloped viruses have the potential to counteract severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) and a wide variety of RNA viruses of pandemic potential.
One promising target is the lipid membrane coating that surrounds enveloped viruses, as membrane disruption
can abrogate viral infectivity. This team’s investigators have developed a new class of AH peptides, and another
new type of self-assembling amphipathic peptoids, that selectively form pores in high-curvature membranes such
as membrane-enveloped virus particles (<160 nm diameter) but do not form pores in low-curvature membranes
such as those of mammalian cells. Once a critical density of pores forms in the viral membrane, pore-induced
membrane lysis occurs, leading to loss of viral infectivity. We have also showed that incorporating D-amino acids
(instead of natural L-amino acids) into LEAD peptides can enhance their in vivo stability. Excitingly, our
preliminary data to date showed that one LEAD peptide (AH-D) has potent antiviral activity against a wide range
of enveloped viruses including Zika virus (ZIKV), Dengue virus (DENV), Chikungunya virus (CHIKV), Yellow
Fever virus (YFV), Japanese encephalitis virus (JEV), and SARS-CoV-2 without cellular toxicity in vitro. Even
more excitingly, when administered in vivo, AH-D peptide can protect mice against lethal ZIKV infections as well
as block DENV viremia. We have also recently developed novel antiviral peptoids that can similarly target viral
envelopes selectively, with potent anti-SARS-CoV-2 activity. Finally, subcutaneous administration of a LEAD
peptide had reasonably comparable exposure but with a longer half-life than when administered intravenously.
We now seek to advance the development of a promising lead molecule by: 1) further characterizing the
biophysical properties of LEAD peptides and peptoids responsible for their antiviral activity against enveloped
viruses; 2) optimizing in vivo pharmacokinetics (PK) of LEAD peptides and peptoids for subcutaneous and
inhalation delivery (by collaborating with Project 2) suitable for outpatient administration; 3) evaluating antiviral
efficacy of the optimized LEAD peptides and peptoids in mouse models of DENV, ZIKV, and SARS-CoV-2; and
4) nominating a top-performing LEAD peptide/peptoid for IND-enabling studies by collaborating with Project 6
on mechanisms of potential resistance to our top performing molecules, conducting synergy studies with other
available DAAs including ones developed in SyneRx, and beginning initial assessments of in vitro ADME and in
vivo non-GLP rat toxicity. Successful completion of our a...

## Key facts

- **NIH application ID:** 10514271
- **Project number:** 1U19AI171421-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nam-Joon Cho
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,909,919
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514271

## Citation

> US National Institutes of Health, RePORTER application 10514271, Targeting viral envelopes with antiviral peptides and peptoids and degraders, and surface proteins with small molecules (1U19AI171421-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10514271. Licensed CC0.

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