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Publication Detail
Unravelling the molecular basis of high affinity nanobodies against HIV p24: in vitro functional, structural and in silico insights.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Gray ER, Brookes JC, Caillat C, Turbé V, Webb BL, Granger LA, Miller BS, McCoy LE, El Khattabi M, Verrips CT, Weiss RA, Duffy DM, Weissenhorn W, McKendry RA
  • Publication date:
    07/06/2017
  • Journal:
    ACS infectious diseases
  • Medium:
    Print-Electronic
  • Print ISSN:
    2373-8227
  • Language:
    eng
Abstract
Preventing the spread of infectious diseases remains an urgent priority worldwide and this is driving the development of advanced nanotechnology to diagnose infections at the point of care. Herein we report the creation of a library of novel nanobody capture ligands to detect p24, one of the earliest markers of HIV infection. We demonstrate that these nanobodies, one tenth the size of conventional antibodies, exhibit high sensitivity and broad specificity to global HIV-1 subtypes. Biophysical characterisation indicates strong 690pM binding constants and fast kinetic on-rates, one to two orders of magnitude better than monoclonal antibody comparators. A crystal structure of the lead nanobody and p24 was obtained, and used alongside molecular dynamics simulations to elucidate the molecular basis of these enhanced performance characteristics. They indicate that binding occurs at C-terminal helices 10 and 11 of p24, a negatively charged region of p24 complemented by the positive surface of the nanobody binding interface involving CDR1, CDR2 and CDR3 loops. Our findings have broad implications on the design of novel antibodies and a wide range of advanced biomedical applications.
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London Centre for Nanotechnology
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Dept of Physics & Astronomy
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London Centre for Nanotechnology
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Div of Infection & Immunity
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London Centre for Nanotechnology
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London Centre for Nanotechnology
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London Centre for Nanotechnology
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Div of Infection & Immunity
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