Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein
Authors: Daniel Fitzgerald
Julien Capin
Sathish K N Yadav
Kapil Gupta
Andrew D Davidson
Adrian J Mulholland
Christine Toelzer
Deborah K Shoemark
Frederic Garzoni
Joachim Spatz
Ufuk Borucu
Imre Berger
Rachel Milligan
Christiane Schaffitzel
Oskar Staufer
Maia Kavanagh Williamson
Journal: Science (2020)
Discipline: Multidisciplinary
Keywords: COVID-19; SARS-CoV-2; spike glycoprotein; linoleic acid; receptor binding domains
Affiliations: School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK., School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, BS8 1TD, UK., Imophoron Ltd, St. Philips Central, Albert Rd, St. Philips, Bristol, BS2 0XJ, UK., Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120 Heidelberg, Germany., School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK., Geneva Biotech Sàrl, Avenue de la Roseraie 64, 1205, Geneva, Switzerland.

Abstract:  Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms that drive high infectivity, broad tissue tropism, and severe pathology. Our 2.85-angstrom cryo-electron microscopy structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains tightly bind the essential free fatty acid linoleic acid (LA) in three composite binding pockets. A similar pocket also appears to be present in the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). LA binding stabilizes a locked S conformation, resulting in reduced angiotensin-converting enzyme 2 (ACE2) interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies that target LA binding by SARS-CoV-2. 

Retracted: No

PubPeer comments:
 It is worth making some general comments on this article. Firstly, that LA supplementation should be discouraged in persons at risk of COVID-19 because LA is directly causal in ARDS, as shown by clinical experience with pneumonia in enteral feeding regimes.[1] Indeed, the USA, with very high COVID-19 death rates, already has an unusually high intake of linoleic acid.[2] However, to offset this negative data, it should be noted that selenium, which in GPx stabilises linoleic acid, is associated with lower COVID-19 death rates, and deficiency of selenium is known to increase virulence and mutation rates of other RNA viruses.[3.4} RNA viruses encode for selenium to produce GPx analogues which keep their genome stable[5]; this depletes host Se and GPx status, leading to reduced immune cell function and increase risk of haemolysis and ARDS caused by release of stored LA as FFA and conversion to leukotoxin. 1} Hegyi P, Szaku00e1cs Z, Sahin-Tu00f3th M. Lipotoxicity and Cytokine Storm in Severe Acute Pancreatitis and COVID-19. Gastroenterology. 2020;159(3):824-827. doi:10.1053 j.gastro.2020.07.014 see also https: www.medpagetoday.com reading-room aga lower-gi 86940 2] Guyenet SJ, Carlson SE. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr. 2015;6(6):660-664. Published 2015 Nov 13. doi:10.3945 an.115.009944 https: www.ncbi.nlm.nih.gov pmc articles PMC4642429 3] Moghaddam A, Heller RA, Sun Q, Seelig J, Cherkezov A, Seibert L, Hackler J, Seemann P, Diegmann J, Pilz M, Bachmann M, Minich WB, Schomburg L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients. 2020 Jul 16;12(7):2098. doi: 10.3390 nu12072098. PMID: 32708526; PMCID: PMC7400921. https: www.mdpi.com 2072-6643 12 7 2098 4] Caroline S Broome, Francis McArdle, Janet AM Kyle, Francis Andrews, Nicola M Lowe, C Anthony Hart, John R Arthur, Malcolm J Jackson, An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status, The American Journal of Clinical Nutrition, Volume 80, Issue 1, July 2004, Pages 154u2013162, https: doi.org 10.1093 ajcn 80.1.154 5] Zhang J, Saad R, Taylor EW, Rayman MP. Selenium and selenoproteins in viral infection with potential relevance to COVID-19. Redox Biol. 2020 Sep 10;37:101715. doi: 10.1016 j.redox.2020.101715. Epub ahead of print. PMID: 32992282; PMCID: PMC7481318. https: pubmed.ncbi.nlm.nih.gov 32992282 ,