A nasal antiviral created by researchers at Columbia University Vagelos College of Physicians and Surgeons blocked the transmission of SARS-CoV-2 in ferrets, suggesting that nasal spray can also prevent infection in people exposed to the new coronavirus, including recent variants
The spray compound – a lipopeptide developed by Matteo Porotto, PhD, and Anne Moscona, MD, professors in the Department of Pediatrics and directors of the Center for Host-Pathogen Interaction – is designed to prevent the new coronavirus from entering the host’s cells.
The antiviral lipopeptide is inexpensive to produce, has a long shelf life and does not require refrigeration. These characteristics set it apart from other developing antiviral approaches, including many monoclonal antibodies. The new nasal lipopeptide may be ideal for curbing the spread of COVID in the United States and globally; the transportable and stable compost can be especially important for rural, low-income and hard-to-reach populations.
The study published in the journal Science on February 17, 2020.
Ferrets, a model for respiratory diseases
Ferrets are often used in studies of respiratory diseases because the lungs of these animals and humans are similar. Ferrets are highly susceptible to SARS-CoV-2 infection, and the virus spreads easily from ferret to ferret.
In this study, carried out in collaboration with Rory de Vries, PhD, and Rik de Swart, PhD, in Erasmus in the Netherlands, 100% of untreated ferrets were infected by their cage companions that eliminate viruses, approaching an environment like sharing a bed or close living conditions for people.
Porotto and Moscona previously created similar lipopeptides – small proteins attached to a cholesterol or tocopherol molecule – to prevent infection of cells by other viruses, including measles, parainfluenza and Nipah viruses. It is a challenge to bring these antiviral compounds to human testing, largely because the infections they avoid are more prevalent or serious in low-income settings.
When SARS-CoV-2 emerged, researchers adapted their designs to the new coronavirus, in collaboration with Christopher Alabi, PhD, at Cornell University. “One lesson we want to emphasize is the importance of applying basic science to develop treatments for viruses that affect human populations worldwide,” say Moscona and Porotto. “The fruits of our previous research have led to our rapid application of methods to COVID-19. “
An article describing a first generation of the compound and its effect on a 3D model of the human lung first appeared in the newspaper mBio on October 20. In this model of human lung, the compound was able to extinguish an initial infection, prevent the spread of the virus in the lung and was non-toxic to airway cells.
Lipopeptides prevent viruses from infecting cells
Lipopeptides work by preventing a virus from fusing with its host’s cell membrane, a necessary step that enveloped viruses, including SARS-CoV-2, use to infect cells. To fuse, the new coronavirus unfolds its peak protein before contracting into a compact bundle that drives fusion.
The compound designed by Porotto and Moscona recognizes the SARS-CoV-2 peak, fits in the unfolded region and prevents the peak protein from adopting the compact form required for fusion.
Anne Moscona and Matteo Porotto. Credit: Center for Host-Pathogen Interaction photo, Columbia University Department of Pediatrics.
In experiments with ferrets in Erasmus, the lipopeptide was applied to the nose of six ferrets. Pairs of treated ferrets were housed with two control ferrets that received nasal spray with saline and a ferret infected with SARS-CoV-2.
After 24 hours of intense direct contact between ferrets, tests revealed that none of the treated ferrets caught the virus from their infected cage companion and their viral load was precisely zero, while all control animals were highly infected.
Lipopeptides are effective against variants
Public health officials are concerned about the emergence of several variants of SARS-CoV-2, which appear to be more transmissible and deadly, and could be more adept at avoiding the antibodies generated by available therapies and vaccines.
Porotto and Moscona tested the lipopeptide in cells infected with a variety of SARS-CoV-2 variants, including B.1.1.7 and B.1.351, and found that the compound prevented the spike protein from all variants from merging with the cell membrane as effectively as the dominant strain.
Lipopeptides are easily administered
Porotto and Moscona propose that these peptides can be used in any situation in which an uninfected person is exposed, whether in a home, school, healthcare environment or community.
“Even in an ideal scenario with large segments of the population vaccinated – and with complete confidence and compliance with vaccination procedures – these antivirals will be an important complement to protect individuals and control transmission”, say Moscona and Porotto. People who cannot be vaccinated or do not develop immunity will particularly benefit from the spray.
Antiviral is easily administered and, based on scientists’ experience with other respiratory viruses, protection would be immediate and would last at least 24 hours.
Scientists are conducting advanced studies on transmission in animal models and on the production and formulation of the peptide. They hope to bring this preventive approach to clinical trials in humans soon, with the ultimate goal of deploying therapy to help contain transmission during this pandemic and to support preparation for future emerging strains and pandemics.
References:
“Intranasal fusion inhibitor lipopeptide prevents the transmission of SARS-CoV-2 by direct contact in ferrets” by Rory D. de Vries, Katharina S. Schmitz, Francesca T. Bovier, Danny Noack, Bart L. Haagmans, Sudipta Biswas, Barry Rockx, Samuel H. Gellman, Christopher A. Alabi, Rik L. de Swart, Anne Moscona and Matteo Porotto, November 5, 2020, bioRxiv.
DOI: 10.1101 / 2020.11.04.361154
“Inhibition of Coronavirus entry In vitro and Ex Vivo by a lipid-conjugated peptide derived from the SARS-CoV-2 domain Spike Glycoprotein HRC ”by Victor K. Outlaw, Francesca T. Bovier, Megan C. Mears, Maria N. Cajimat, Yun Zhu, Michelle J. Lin, Amin Addetia, Nicole AP Lieberman, Vikas Peddu, Xuping Xie, Pei-Yong Shi, Alexander L. Greninger, Samuel H. Gellman, Dennis A. Bente, Anne Moscona, Matteo Porotto, October 20, 2020, +mBio.
DOI: 10.1128 / mBio.01935-20
Anne Moscona, MD, is Sherie L. Morrison Professor of Immunology (in Microbiology and Immunology), professor of pediatrics and professor of physiology and cell biophysics at Columbia University’s Faculty of Vaginal Physicians and Surgeons.
Matteo Porotto, PhD, is an associate professor of viral molecular pathogenesis in the Department of Pediatrics at Columbia University’s Faculty of Vaginal Physicians and Surgeons.
Other authors: Rory D. de Vries (Medical Center at Erasmus University, Netherlands), Katharina S. Schmitz (Erasmus), Francesca T. Bovier (Columbia University Irving Medical Center and Campania University “Luigi Vanvitelli”, Italy), Danny Noack (Erasmus), Bart L. Haagmans (Erasmus), Sudipta Biswas (Cornell University), Barry Rockx (Erasmus), Samuel H. Gellman (University of Wisconsin, Madison), Christopher A. Alabi (Cornell) and Rik L. of Swart (Erasmus).
This work was supported by the National Institutes of Health (AI146980, AI121349, NS091263 and AI114736), the Sharon Golub Fund at Columbia University Irving Medical Center, the Children’s Health Innovation Nucleation Fund of the Pediatrics Department at CUIMC and a COVID -19 Research Award from the Harrington Discovery Institute at University Hospitals.
Anne Moscona, Matteo Porotto, Rory de Vries, Francesca Bovier and Rik de Swart are listed as inventors in a provisional patent application covering the findings reported in this article.