# Targeting SARS-Related Coronaviruses with a D-peptide Entry Inhibitor

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $429,481

## Abstract

Project Summary
 The 21st century has seen the emergence of multiple lethal human coronaviruses (SARS-CoV, MERS-CoV,
and now SARS-CoV-2). There is an urgent need for therapeutic options to combat the current and inevitable
future SARS-like pandemics. Coronaviruses infect cells using a conserved entry mechanism shared by viruses
across multiple families (including HIV, Ebola, and influenza) in which two regions of the trimeric viral spike
protein (HR1 and HR2) collapse to form a highly stable six-helix bundle structure that forces the viral and
cellular membranes together, inducing membrane fusion. Inhibitor binding to HR1 blocks six-helix bundle
formation and stops viral entry, preventing infection. Our lab specializes in mirror-image phage display (MIPD),
an innovative approach to identify novel synthetic protease-resistant D-peptide drug candidates, with a special
focus on the inhibition of viral entry (with our HIV-1 drug, CPT31, set to begin clinical trials). D-peptides
(peptides composed of mirror-image D-amino acids) cannot be digested by proteases in the body and,
therefore, possess significant therapeutic advantages including extended half-life, lower dosing, reduced
immunogenicity (not digested for MHC presentation), and durability in protease-rich environments such as the
respiratory tract. To address the current health crisis, we are expediting our drug discovery process to identify
D-peptide entry inhibitors that target the conserved HR1 of SARS-related coronaviruses. We have designed,
synthesized, and characterized our HR1 mimic drug targets and are using them in MIPD to identify D-peptide
inhibitors of 6-helix bundle formation and viral entry.
 In this proposal, we will chemically synthesize the D-peptides identified by MIPD and characterize their
target affinity (using surface plasmon resonance) and antiviral activity against SARS-CoV and SARS-CoV-2
pseudoviruses. Promising D-peptides will be affinity-matured using a second round of MIPD to optimize
potency. Using our custom-designed PEG scaffold (the backbone of CPT31), we will trimerize the highest
affinity D-peptide candidates to improve avidity for the trimeric spike target and attach a membrane-localizing
group, such as cholesterol, that will enrich the D-peptide at the cellular site of viral entry and improve in vivo
half-life. These leading D-peptides will be tested against authentic virus (in collaboration with USU's Institute
for Antiviral Research). Our objective is to have one D-peptide candidate with ≤100 nM in vitro EC90 against
SARS-CoV-2 and SARS and a good therapeutic index (EC50/CC50 >100) to advance to in vivo PK and efficacy
studies, using USU's hamster model of SARS-CoV-2 infection. At the end of the grant period, we expect to
have one D-peptide lead with demonstrated in vivo animal efficacy, poised for IND-enabling preclinical studies
and development as a SARS-related coronavirus treatment and/or preventative.

## Key facts

- **NIH application ID:** 10189371
- **Project number:** 1R21AI158568-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Michael S Kay
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,481
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189371

## Citation

> US National Institutes of Health, RePORTER application 10189371, Targeting SARS-Related Coronaviruses with a D-peptide Entry Inhibitor (1R21AI158568-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189371. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*