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Unravelling the molecular basis of high affinity nanobodies against HIV p24: in vitro functional, structural and in silico insights

Gray, ER; Brookes, JC; Caillat, C; Turbé, V; Webb, BL; Granger, LA; Miller, BS; ... McKendry, RA; + view all (2017) Unravelling the molecular basis of high affinity nanobodies against HIV p24: in vitro functional, structural and in silico insights. ACS Infectious Diseases , 3 (7) pp. 479-491. 10.1021/acsinfecdis.6b00189. Green open access

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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.

Type: Article
Title: Unravelling the molecular basis of high affinity nanobodies against HIV p24: in vitro functional, structural and in silico insights
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acsinfecdis.6b00189
Publisher version: http://doi.org/10.1021/acsinfecdis.6b00189
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: HIV, nanobody, high-affinity, molecular dynamics, p24, crystal structure
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > London Centre for Nanotechnology
URI: http://discovery.ucl.ac.uk/id/eprint/1559875
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