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Interactions of SARS-CoV-2 envelope protein with amilorides correlate with antiviral activity.
Park, Sang Ho; Siddiqi, Haley; Castro, Daniela V; De Angelis, Anna A; Oom, Aaron L; Stoneham, Charlotte A; Lewinski, Mary K; Clark, Alex E; Croker, Ben A; Carlin, Aaron F; Guatelli, John; Opella, Stanley J.
  • Park SH; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
  • Siddiqi H; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
  • Castro DV; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
  • De Angelis AA; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
  • Oom AL; Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
  • Stoneham CA; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
  • Lewinski MK; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
  • Clark AE; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
  • Croker BA; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
  • Carlin AF; Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
  • Guatelli J; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
  • Opella SJ; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
PLoS Pathog ; 17(5): e1009519, 2021 05.
Article in English | MEDLINE | ID: covidwho-1232468
Preprint
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ABSTRACT
SARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19, a sometimes-lethal respiratory infection responsible for a world-wide pandemic. The envelope (E) protein, one of four structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein consists of a long transmembrane helix (residues 8-43) and a short cytoplasmic helix (residues 53-60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6-18) is the principal binding site. The binding affinity of the inhibitors to E protein in micelles correlates with their antiviral potency in Vero E6 cells HMA ≈ EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5' position of the amiloride pyrazine ring play essential roles in binding to E protein and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein and for structure-based drug discovery targeting this protein.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Amiloride / Coronavirus Envelope Proteins / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009519

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Amiloride / Coronavirus Envelope Proteins / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009519