CXCR4-targeting nanobodies differentially inhibit CXCR4 function and HIV entry

Autor: Joseph B. Rucker, Dominique Schols, Martine J. Smit, Chris de Graaf, Marta Arimont, Tom Van Loy, Jordi Doijen, Kurt Vermeire, Vladimir Bobkov, Hans de Haard, Rebecca Rimkunas, Tracy M. Handel, Chunxia Zhao, Theo Verrips, Anneleen Van Hout, Raimond Heukers, Alex Klarenbeek, Bas van der Woning
Přispěvatelé: AIMMS, Medicinal chemistry
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Biochemical Pharmacology, 158, 402-412. Elsevier Inc.
Van Hout, A, Klarenbeek, A, Bobkov, V, Doijen, J, Arimont, M, Zhao, C, Heukers, R, Rimkunas, R, de Graaf, C, Verrips, T, van der Woning, B, de Haard, H, Rucker, J B, Vermeire, K, Handel, T, Van Loy, T, Smit, M J & Schols, D 2018, ' CXCR4-targeting nanobodies differentially inhibit CXCR4 function and HIV entry ', Biochemical Pharmacology, vol. 158, pp. 402-412 . https://doi.org/10.1016/j.bcp.2018.10.015
Biochemical Pharmacology
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2018.10.015
Popis: The chemokine receptor CXCR4 and its ligand CXCL12 contribute to a variety of human diseases, such as cancer. CXCR4 is also a major co-receptor facilitating HIV entry. Accordingly, CXCR4 is considered as an attractive therapeutic target. Drug side effects and poor pharmacokinetic properties have been major hurdles that have prevented the implementation of CXCR4-directed inhibitors in treatment regimes. We evaluated the activity of a new and promising class of biologics, namely CXCR4-targeting nanobodies, with the purpose of identifying nanobodies that would preferentially inhibit HIV infection, while minimally disturbing other CXCR4-related functions. All CXCR4-interacting nanobodies inhibited CXCL12 binding and receptor-mediated calcium mobilization with comparable relative potencies. Importantly, the anti-HIV-1 activity of the nanobodies did not always correlate with their ability to modulate CXCR4 signaling and function, indicating that the anti-HIV and anti-CXCR4 activity are not entirely overlapping and may be functionally separated. Three nanobodies with divergent activity profiles (VUN400, VUN401 and VUN402) were selected for in depth biological evaluation. While all three nanobodies demonstrated inhibitory activity against a wide range of HIV (X4) strains, VUN402 poorly blocked CXCL12-induced CXCR4 internalization, chemotaxis and changes in cell morphology. Each of these nanobodies recognized distinct, although partially overlapping epitopes on CXCR4, which might underlie their distinct activity profiles. Our results demonstrate the potential of CXCR4-targeting nanobody VUN402 as a novel lead and starting point for the development of a more potent and selective anti-HIV agent.
Databáze: OpenAIRE
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