Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets
Authors: Sudipta Biswas
Barry Rockx
Rory D de Vries
Bart L Haagmans
Christopher A Alabi
Gaël McGill
Kyle N Stearns
Rik L de Swart
Katharina S Schmitz
Camilla Predella
Samuel H Gellman
Matteo Porotto
Anne Moscona
Sander Herfst
N Valerio Dorrello
Francesca T Bovier
Danny Noack
Jonathan Khao
Jennifer Drew-Bear
Journal: Science (2021)
Discipline: Multidisciplinary
Keywords: COVID-19 pandemic; viral transmission; SARS-CoV-2; membrane fusion; spike protein
Affiliations: Department of Viroscience, Erasmus MC, Rotterdam, Netherlands., Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Caserta, Italy., Department of Biomedical Engineering, Politecnico di Milano, Milan, Italy., Digizyme Inc., Brookline, MA, USA., Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA., Center for Molecular and Cellular Dynamics, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA., Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA. caa238@cornell.edu   ., Department of Viroscience, Erasmus MC, Rotterdam, Netherlands. caa238@cornell.edu   ., Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. caa238@cornell.edu   ., Department of Microbiology and Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Abstract:  Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2. 

Retracted: No

PubPeer comments:
 1. The major issue is to do with the peptide and how it was prepared. We do not dissolve peptides in water and in this case, it is not clear as to its overall solubility or insolubility, and their effects on the obtained results. This renders the observations rather questionable. 2. The in vitro data performed using a pseudo-viral particle based on lenti is also questionable is to what it exactly means. The authors could have used a live SARSCoV2 virus in their assays. 3. The ferret data remains questionable as to the dosing and what exactly was soluble in the ferret nostril. How did the authors convert Ct values to viral load? 4. The mice data and the presence of the peptide in the lung is rather convenient when the authors dosed the mice at a total dose of 240 ug instead of the claimed 100 ug by the authors. 5. No data was presented confirming target engagement this peptide and its binding to the spike protein, why is that? 6. If truly this peptide binds to the spike protein and blocks fusion, what happens to the inactive complex? The ferret data shows virus reduction in the nostrils, meaning that the virus is shedding? , 
 I read few times this paper and came to the conclusion that the data is super super clean to be true; especially the ferret experiments under figure 4. It is just difficult to reconcile that an antiviral would take up to 5 days to reduce the virus in the noise and throat, whereas this group of authors would like us to believe that an insoluble peptide squirted in the noise would reduce viral load in less than a day (figure 3B)? With few exceptions, peptide treated ferrets had no virus detected? Then I thought about how this peptide would interact with the HRC region of the virus, I could not see how an unstructured insoluble peptide would not only recognize a trimeric alpha helical structure of the HRC region and bind to it as depicted in figure 1G without any supporting evidence? This sounds more like a u201chomeotherapeuticu201d water effect since this miracle peptide is dissolved in water. It is unfortunate that high profile journal keep publishing such opportunistic work during this covid19 pandemic. ,