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Título: | Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile |
Autor: | Rujas, Edurne CSIC ORCID; Leaman, Daniel P.; Insausti, Sara CSIC ORCID; Carravilla, Pablo CSIC ORCID; García-Porras, Miguel CSIC; Largo, Eneko CSIC ORCID; Morillo, Izaskun CSIC ORCID; Sánchez-Eugenia, Rubén CSIC ORCID; Zhang, Lei; Cui, Hong; Iloro, Ibon CSIC ORCID; Elortza, Félix; Julien, Jean-Philippe; Eggeling, Christian; Zwick, Michael B.; Caaveiro, José M. M.; Nieva, José Luis CSIC ORCID | Palabras clave: | Immunology Virology |
Fecha de publicación: | 24-sep-2021 | Editor: | Cell Press | Citación: | iScience 24(9): 102987 (2021) | Resumen: | Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associated with the presence of autoreactivity/polyreactivity, a property that can limit their use as therapeutic agents. The bnAb 4E10, targeting the conserved Membrane proximal external region (MPER) of HIV-1, displays almost pan-neutralizing activity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the third complementarity-determining region of the heavy chain (CDRH3) loop, which is essential for viral neutralization, critically contributes to this detrimental effect. Here, we have replaced the aromatic/hydrophobic residues from the apex of the CDRH3 of 4E10 with a single aromatic molecule through chemical modification to generate a variant that preserves the neutralization potency and breadth of 4E10 but with reduced autoreactivity. Collectively, our study suggests that the localized accumulation of aromaticity by chemical modification provides a pathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs. | Versión del editor: | https://doi.org/10.1016/j.isci.2021.102987 | URI: | http://hdl.handle.net/10261/311050 | DOI: | 10.1016/j.isci.2021.102987 | E-ISSN: | 2589-0042 |
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Focal_accumulation_Rujas.pdf | 3,68 MB | Adobe PDF | Visualizar/Abrir |
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