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Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins.
Lam, Kwok-Ho; Tremblay, Jacqueline M; Vazquez-Cintron, Edwin; Perry, Kay; Ondeck, Celinia; Webb, Robert P; McNutt, Patrick M; Shoemaker, Charles B; Jin, Rongsheng.
Affiliation
  • Lam KH; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
  • Tremblay JM; Tufts Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
  • Vazquez-Cintron E; Department of Neuroscience, U.S. Army Medical Research Institute of Chemical Defense, Gunpowder, MD 21010, USA.
  • Perry K; NE-CAT, Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, IL 60439, USA.
  • Ondeck C; Department of Neuroscience, U.S. Army Medical Research Institute of Chemical Defense, Gunpowder, MD 21010, USA.
  • Webb RP; The Division of Molecular and Translational Sciences, United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, MD 21702, USA.
  • McNutt PM; Department of Neuroscience, U.S. Army Medical Research Institute of Chemical Defense, Gunpowder, MD 21010, USA.
  • Shoemaker CB; Tufts Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
  • Jin R; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: r.jin@uci.edu.
Cell Rep ; 30(8): 2526-2539.e6, 2020 02 25.
Article in En | MEDLINE | ID: mdl-32101733
Botulinum neurotoxin (BoNT) is one of the most acutely lethal toxins known to humans, and effective treatment for BoNT intoxication is urgently needed. Single-domain antibodies (VHH) have been examined as a countermeasure for BoNT because of their high stability and ease of production. Here, we investigate the structures and the neutralization mechanisms for six unique VHHs targeting BoNT/A1 or BoNT/B1. These studies reveal diverse neutralizing mechanisms by which VHHs prevent host receptor binding or block transmembrane delivery of the BoNT protease domain. Guided by this knowledge, we design heterodimeric VHHs by connecting two neutralizing VHHs via a flexible spacer so they can bind simultaneously to the toxin. These bifunctional VHHs display much greater potency in a mouse co-intoxication model than similar heterodimers unable to bind simultaneously. Taken together, our studies offer insight into antibody neutralization of BoNTs and advance our ability to design multivalent anti-pathogen VHHs with improved therapeutic properties.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Botulinum Toxins / Antitoxins / Drug Design / Single-Domain Antibodies Limits: Animals Language: En Journal: Cell Rep Year: 2020 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Botulinum Toxins / Antitoxins / Drug Design / Single-Domain Antibodies Limits: Animals Language: En Journal: Cell Rep Year: 2020 Document type: Article Affiliation country: United States Country of publication: United States