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dc.contributor.authorJurado, Samuel
dc.contributor.authorMoog, Christiane
dc.contributor.authorCano-Muñoz, Mario
dc.contributor.authorSchmidt, Sylvie
dc.contributor.authorLaumond, Géraldine
dc.contributor.authorRuocco, Valentina
dc.contributor.authorPolo-Megías, Daniel
dc.contributor.authorConejero Lara, Francisco 
dc.contributor.authorMorel, Bertrand
dc.date.accessioned2021-03-09T12:14:29Z
dc.date.available2021-03-09T12:14:29Z
dc.date.issued2020
dc.identifier.citationJurado 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.2020.08.010es_ES
dc.identifier.urihttp://hdl.handle.net/10481/67027
dc.description.abstractOne 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.sponsorshipSpanish 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.sponsorshipDepartamento de Química Física, Facultad de Ciencias, Universidad de Granada. Grupo FQM-171 "Biofísica y Biotecnología Molecular"es_ES
dc.language.isoenges_ES
dc.publisherELSEVIERes_ES
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 3.0 Licensees_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es_ES
dc.subjectFusion inhibitorses_ES
dc.subjectBinding affinityes_ES
dc.subjectCoiled-coiles_ES
dc.subjectEnvelope glycoproteines_ES
dc.subjectHydrophobic pocketes_ES
dc.titleProbing vulnerability of the gp41 C-terminal heptad repeat as target for miniprotein HIV inhibitorses_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES
dc.identifier.doi10.1016/j.jmb.2020.08.010
dc.type.hasVersioninfo:eu-repo/semantics/draftes_ES


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