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Probing vulnerability of the gp41 C-terminal heptad repeat as target for miniprotein HIV inhibitors
dc.contributor.author | Jurado, Samuel | |
dc.contributor.author | Moog, Christiane | |
dc.contributor.author | Cano Muñoz, Mario | |
dc.contributor.author | Schmidt, Sylvie | |
dc.contributor.author | Laumond, Géraldine | |
dc.contributor.author | Ruocco, Valentina | |
dc.contributor.author | Polo-Megías, Daniel | |
dc.contributor.author | Conejero Lara, Francisco | |
dc.contributor.author | Morel, Bertrand | |
dc.date.accessioned | 2021-03-09T12:14:29Z | |
dc.date.available | 2021-03-09T12:14:29Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Jurado S, Moog C, Cano-Muñoz M, Schmidt S, Laumond G, Ruocco V, Standoli S, Polo-Megías D, Conejero-Lara F, Morel B. Probing Vulnerability of the gp41 C-Terminal Heptad Repeat as Target for Miniprotein HIV Inhibitors. J Mol Biol. 2020 Sep 18;432(20):5577-5592. doi: 10.1016/j.jmb.2020.08.010 | es_ES |
dc.identifier.uri | http://hdl.handle.net/10481/67027 | |
dc.description.abstract | One of the therapeutic strategies in HIV neutralization is blocking membrane fusion. In this process, tight interaction between the N-terminal and C-terminal heptad-repeat (NHR and CHR) regions of gp41 is essential to promote membranes apposition and merging. We have previously developed single-chain proteins (named covNHR) that accurately mimic the complete gp41 NHR region in its trimeric conformation. They tightly bind CHR-derived peptides and show a potent and broad HIV inhibitory activity in vitro. However, the extremely high binding affinity (sub-picomolar) is not in consonance with their inhibitory activity (nanomolar), likely due to partial or temporal accessibility of their target in the virus. Here, we have designed and characterized two single-chain covNHR miniproteins each encompassing one of the two halves of the NHR region and containing two of the four sub-pockets of the NHR crevice. The two miniproteins fold as trimeric helical bundles as expected but while the C-terminal covNHR (covNHR-C) miniprotein is highly stable, the N-terminal counterpart (covNHR-N) shows only marginal stability that could be improved by engineering an internal disulfide bond. Both miniproteins bind their respective complementary CHR peptides with moderate (micromolar) affinity. Moreover, the covNHR-N miniproteins can access their target in the context of trimeric native envelope proteins and show significant inhibitory activity for several HIV pseudoviruses. In contrast, covNHR-C cannot bind its target sequence and neither inhibits HIV, indicating a higher vulnerability of C-terminal part of CHR. These results may guide the development of novel HIV inhibitors targeting the gp41 CHR region. | es_ES |
dc.description.sponsorship | Spanish Ministry of Economy and Competitiveness (grant: BIO2016-76640-R), ANRS and the Vaccine Research Institute for the Investissements d'Avenir program to C.M. and by the European Fund for Research and Development from the European Union. | es_ES |
dc.description.sponsorship | Departamento de Química Física, Facultad de Ciencias, Universidad de Granada. Grupo FQM-171 "Biofísica y Biotecnología Molecular" | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | ELSEVIER | es_ES |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | es_ES |
dc.subject | Fusion inhibitors | es_ES |
dc.subject | Binding affinity | es_ES |
dc.subject | Coiled-coil | es_ES |
dc.subject | Envelope glycoprotein | es_ES |
dc.subject | Hydrophobic pocket | es_ES |
dc.title | Probing vulnerability of the gp41 C-terminal heptad repeat as target for miniprotein HIV inhibitors | es_ES |
dc.type | journal article | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.identifier.doi | 10.1016/j.jmb.2020.08.010 | |
dc.type.hasVersion | AO | es_ES |