Development of a Multivalent Macrocyclic Peptide that Protects Against SARS-CoV-2 Infection Following Intranasal Administration
6 affiliations
- 1Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam, Netherlands, 1081 HV
- 2Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, Krakow, Poland, 30-387
- 3Faculty of Veterinary Medicine
- 4Utrecht University
- 5VirXcel B.V., Valeriusstraat 155 H, Amsterdam, 1075EV
- 6Department of Chemical Biology, German Center for Infection Research, Inhoffenstrasse 7, Braunschweig, Germany, 38124
Abstract
The risk of zoonotic spillover of coronaviruses poses a constant threat to humanity, as recently exemplified by SARS‑CoV-2. During the pandemic, the rapid emergence of immune escape mutations led to a loss of efficacy of both therapeutic and humoral anti‑spike antibodies, emphasizing the need for therapeutics that engage binding sites within the spike protein that are both conserved among related viruses and not under selective pressure from immune surveillance. Here, we report the development of a first-in-class fusion inhibitor cyclic peptide that targets such a site. Guided by a deep mutational scan of our earlier mRNA display hit we arrived at an analogue with 5 mutations that retains broad activity within the subgenus sarbecovirus, including against SARS-CoV-1, but shows up to 50-fold improved potency and approximately 25-fold improved solubility. Multimerization further improved IC50 by one order of magnitude to give a tetrameric construct (H4v1Az)4 that inhibits Omicron BA.2.86 replication with an IC50 of approximately 10 nM in cellular assays, including human airway epithelial cell primary cultures. Moreover, (H4v1Az)4 demonstrated significant antiviral efficacy in vivo in a Syrian golden hamster model following combined pre- and post-exposure prophylactic intranasal administration. This multimeric peptide represents a promising broadly active candidate suitable both for treatment of SARS-CoV-2 infection and for preparedness against future emerging sarbecoviruses.
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BibTeX
@misc{hopstaken2026development,
title = {{Development of a Multivalent Macrocyclic Peptide that Protects Against SARS-CoV-2 Infection Following Intranasal Administration}},
author = {Antonius J.P. Hopstaken and Aneta Zegar and Oliver J. Debski-Antoniak and Preeti Hooda and Aleksandra Milewska and Melissa van Dortmondt and Joline van der Lee and Minglong Liu and Pieter Jan Vos and Peter J.M. Rottier and Katharina Rox and Krzysztof Pyrć and Berend-Jan Bosch and Frank J.M. van Kuppeveld and Daniel L. Hurdiss and Seino A.K. Jongkees},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15003355/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003355/v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Development of a Multivalent Macrocyclic Peptide that Protects Against SARS-CoV-2 Infection Following Intranasal Administration
AU - Antonius J.P. Hopstaken
AU - Aneta Zegar
AU - Oliver J. Debski-Antoniak
AU - Preeti Hooda
AU - Aleksandra Milewska
AU - Melissa van Dortmondt
AU - Joline van der Lee
AU - Minglong Liu
AU - Pieter Jan Vos
AU - Peter J.M. Rottier
AU - Katharina Rox
AU - Krzysztof Pyrć
AU - Berend-Jan Bosch
AU - Frank J.M. van Kuppeveld
AU - Daniel L. Hurdiss
AU - Seino A.K. Jongkees
PY - 2026
DA - 2026/09/28
PB - ChemRxiv
DO - 10.26434/chemrxiv.15003355/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003355/v2
AB - The risk of zoonotic spillover of coronaviruses poses a constant threat to humanity, as recently exemplified by SARS‑CoV-2. During the pandemic, the rapid emergence of immune escape mutations led to a loss of efficacy of both therapeutic and humoral anti‑spike antibodies, emphasizing the need for therapeutics that engage binding sites within the spike protein that are both conserved among related viruses and not under selective pressure from immune surveillance. Here, we report the development of a first-in-class fusion inhibitor cyclic peptide that targets such a site. Guided by a deep mutational scan of our earlier mRNA display hit we arrived at an analogue with 5 mutations that retains broad activity within the subgenus sarbecovirus, including against SARS-CoV-1, but shows up to 50-fold improved potency and approximately 25-fold improved solubility. Multimerization further improved IC50 by one order of magnitude to give a tetrameric construct (H4v1Az)4 that inhibits Omicron BA.2.86 replication with an IC50 of approximately 10 nM in cellular assays, including human airway epithelial cell primary cultures. Moreover, (H4v1Az)4 demonstrated significant antiviral efficacy in vivo in a Syrian golden hamster model following combined pre- and post-exposure prophylactic intranasal administration. This multimeric peptide represents a promising broadly active candidate suitable both for treatment of SARS-CoV-2 infection and for preparedness against future emerging sarbecoviruses.
ER -