Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape.

Autor:	Mast FD; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States., Fridy PC; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States., Ketaren NE; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States., Wang J; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States., Jacobs EY; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States.; Department of Chemistry, St. John's University, Queens, United States., Olivier JP; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States., Sanyal T; Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States., Molloy KR; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States., Schmidt F; Laboratory of Retrovirology, The Rockefeller University, New York, United States., Rutkowska M; Laboratory of Retrovirology, The Rockefeller University, New York, United States., Weisblum Y; Laboratory of Retrovirology, The Rockefeller University, New York, United States., Rich LM; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States., Vanderwall ER; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States., Dambrauskas N; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States., Vigdorovich V; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States., Keegan S; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States., Jiler JB; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States., Stein ME; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States., Olinares PDB; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States., Herlands L; AbOde Therapeutics Inc, Woods Hole, United States., Hatziioannou T; Laboratory of Retrovirology, The Rockefeller University, New York, United States., Sather DN; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.; Department of Pediatrics, University of Washington, Seattle, United States., Debley JS; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States.; Department of Pediatrics, University of Washington, Seattle, United States.; Division of Pulmonary and Sleep Medicine, Seattle Children's Hospital, Seattle, United States., Fenyö D; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States., Sali A; Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States., Bieniasz PD; Laboratory of Retrovirology, The Rockefeller University, New York, United States.; Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Aitchison JD; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.; Department of Pediatrics, University of Washington, Seattle, United States.; Department of Biochemistry, University of Washington, Seattle, United States., Chait BT; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States., Rout MP; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Dec 07; Vol. 10. Date of Electronic Publication: 2021 Dec 07.
DOI:	10.7554/eLife.73027
Abstrakt:	The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophylactic strategies. Competing Interests: FM, PF, NK, JW, EJ, JO, JA, BC, MR Inventor on a provisional patent describing the anti-spike nanobodies described in this manuscript, TS, KM, FS, MR, YW, LR, EV, ND, VV, SK, JJ, MS, PO, TH, DS, JD, DF, AS, PB No competing interests declared, LH Louis Herlands is affiliated with AbOde Therapeutics Inc. The author has no financial interests to declare (© 2021, Mast et al.)
Databáze:	MEDLINE
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