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The free fatty acid-binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron.
Sci Adv. 2022 11 25; 8(47):eadc9179.SA

Abstract

As coronavirus disease 2019 (COVID-19) persists, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2, and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation, while the open, infectious conformation is devoid of LA. Electron tomography of SARS-CoV-2-infected cells reveals that LA treatment inhibits viral replication, resulting in fewer deformed virions. Our results establish FFA binding as a hallmark of pathogenic β-CoV infection and replication, setting the stage for FFA-based antiviral strategies to overcome COVID-19.

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Authors+Show Affiliations

Toelzer C
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Gupta K
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK. Imophoron Ltd., St. Philips Central, Albert Rd, Bristol BS2 0XJ, UK.
Yadav SKN
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Hodgson L
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Williamson MK
Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Buzas D
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK. Max Planck Bristol Centre for Minimal Biology, Cantock's Close, Bristol BS8 1TS, UK.
Borucu U
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Powers K
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Stenner R
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Vasileiou K
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Garzoni F
Imophoron Ltd., St. Philips Central, Albert Rd, Bristol BS2 0XJ, UK.
Fitzgerald D
Halo Therapeutics Ltd., St. Philips Central, Albert Rd, Bristol BS2 0XJ, UK.
Payré C
Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia Antipolis, France.
Gautam G
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Lambeau G
Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia Antipolis, France.
Davidson AD
Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Verkade P
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK.
Frank M
Biognos AB, Box 8963, 40274 Göteborg, Sweden.
Berger I
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK. Max Planck Bristol Centre for Minimal Biology, Cantock's Close, Bristol BS8 1TS, UK. Halo Therapeutics Ltd., St. Philips Central, Albert Rd, Bristol BS2 0XJ, UK. School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
Schaffitzel C
School of Biochemistry, University of Bristol, 1 Tankard's Close, Bristol BS8 1TD, UK. Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK. Halo Therapeutics Ltd., St. Philips Central, Albert Rd, Bristol BS2 0XJ, UK.

MeSH

HumansSpike Glycoprotein, CoronavirusFatty Acids, NonesterifiedCOVID-19SARS-CoV-2

Pub Type(s)

Journal Article

Language

eng

PubMed ID

36417532

Citation

Toelzer, Christine, et al. "The Free Fatty Acid-binding Pocket Is a Conserved Hallmark in Pathogenic Β-coronavirus Spike Proteins From SARS-CoV to Omicron." Science Advances, vol. 8, no. 47, 2022, pp. eadc9179.
Toelzer C, Gupta K, Yadav SKN, et al. The free fatty acid-binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron. Sci Adv. 2022;8(47):eadc9179.
Toelzer, C., Gupta, K., Yadav, S. K. N., Hodgson, L., Williamson, M. K., Buzas, D., Borucu, U., Powers, K., Stenner, R., Vasileiou, K., Garzoni, F., Fitzgerald, D., Payré, C., Gautam, G., Lambeau, G., Davidson, A. D., Verkade, P., Frank, M., Berger, I., & Schaffitzel, C. (2022). The free fatty acid-binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron. Science Advances, 8(47), eadc9179. https://doi.org/10.1126/sciadv.adc9179
Toelzer C, et al. The Free Fatty Acid-binding Pocket Is a Conserved Hallmark in Pathogenic Β-coronavirus Spike Proteins From SARS-CoV to Omicron. Sci Adv. 2022 11 25;8(47):eadc9179. PubMed PMID: 36417532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The free fatty acid-binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron. AU - Toelzer,Christine, AU - Gupta,Kapil, AU - Yadav,Sathish K N, AU - Hodgson,Lorna, AU - Williamson,Maia Kavanagh, AU - Buzas,Dora, AU - Borucu,Ufuk, AU - Powers,Kyle, AU - Stenner,Richard, AU - Vasileiou,Kate, AU - Garzoni,Frederic, AU - Fitzgerald,Daniel, AU - Payré,Christine, AU - Gautam,Gunjan, AU - Lambeau,Gérard, AU - Davidson,Andrew D, AU - Verkade,Paul, AU - Frank,Martin, AU - Berger,Imre, AU - Schaffitzel,Christiane, Y1 - 2022/11/23/ PY - 2022/11/23/entrez PY - 2022/11/24/pubmed PY - 2022/11/26/medline SP - eadc9179 EP - eadc9179 JF - Science advances JO - Sci Adv VL - 8 IS - 47 N2 - As coronavirus disease 2019 (COVID-19) persists, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2, and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation, while the open, infectious conformation is devoid of LA. Electron tomography of SARS-CoV-2-infected cells reveals that LA treatment inhibits viral replication, resulting in fewer deformed virions. Our results establish FFA binding as a hallmark of pathogenic β-CoV infection and replication, setting the stage for FFA-based antiviral strategies to overcome COVID-19. SN - 2375-2548 UR - https://www.unboundmedicine.com/medline/citation/36417532/The_free_fatty_acid_binding_pocket_is_a_conserved_hallmark_in_pathogenic_β_coronavirus_spike_proteins_from_SARS_CoV_to_Omicron_ DB - PRIME DP - Unbound Medicine ER -