%0 Journal Article %T Structure-based optimization of a PDZ binding motif within a viral peptide stimulates neurite outgrowth %+ Neuro-Immunologie Virale - Viral Neuro-immunology %+ Résonance Magnétique Nucléaire des Biomolécules %+ Institut du Cerveau = Paris Brain Institute (ICM) %+ Architecture et fonction des macromolécules biologiques (AFMB) %+ Institut Pasteur [Paris] (IP) %A Khan, Zakir %A Terrien, Elouan %A Delhommel, Florent %A Lefebvre-Omar, Cynthia %A Bohl, Delphine %A Vitry, Sandrine %A Bernard, Clara %A Ramirez, Juan, Morua %A Chaffotte, Alain %A Ricquier, Kevin %A Vincentelli, Renaud %A Buc, Henri %A Préhaud, Christophe %A Wolff, Nicolas %A Lafon, Monique %Z This work was supported by the following grants: ANR (Agence Nationale de la Recherche), BSV8- 0008-01 MAST-2-PTEN. AFM (Association Française contre les Myopathies) Characterization of pathological defects in motor neurons derived from patients Amyotrophic Lateral Sclerosis (ALS). Grand Prix de l’Académie des Sciences/Fondation Générale de Santé, and Incentive grant from Institut Carnot -Pasteur Maladies Infectieuses Unraveling the neuroprotective functions and optimization of new neuroprotective compound . The research leading to the results on IP SC has received funding from the programs Investissements d’Avenir ANR -10- IAIHU -06 and ANR -11- INBS -0011- NeurATRIS : Translational Research Infrastructure for Biotherapies in Neurosciences. ET and FD are recipients of PhD fellowships from the Ministère de l’ Enseignement Supérieur et de la Recherche. CL-O was supported by a PhD fellowship from Revive (ANR -10 -LABX -73). We thank Sylviane Hoos (Biophysics Core, Institut Pasteur) for ITC expertise and the team of the Technology Core of the Center for Translational Science (CRT), Institut Pasteur, for their help our with the Incucyte Technology. %< avec comité de lecture %@ 0021-9258 %J Journal of Biological Chemistry %I American Society for Biochemistry and Molecular Biology %V 294 %N 37 %P 137555-13768 %8 2019-07 %D 2019 %R 10.1074/jbc.RA119.008238 %M 31346033 %K neurite outgrowth %K protein-protein interaction %K neurodegenerative diseases %K serine/threonine protein kinase %K structure function analysis %K therapeutical drug candidate %K Nuclear Magnetic Resonance %K viral protein %K Interfering peptide %K PDZ domain %Z Cognitive science %Z Cognitive science/NeuroscienceJournal articles %X Protection of neuronal homeostasis is a major goal in the management of neurodegenerative diseases. Microtubule-associated Ser/Thre kinase 2 (MAST2), inhibits neurite outgrowth, and its inhibition therefore represents a potential therapeutic strategy. We previously reported that a viral protein (G-protein from rabies virus) capable of interfering with protein-protein interactions between the PDZ domain of MAST2 and the C-terminal moieties of its cellular partners counteracts MAST2-mediated suppression of neurite outgrowth. Here, we designed peptides derived from the native viral protein to increase the affinity of these peptides for the MAST2 PDZ domain. Our strategy involved modifying the length and flexibility of the non-interacting sequence linking the two subsites anchoring the peptide to the PDZ domain. Three peptides, Neurovita1 (NV1), NV2, and NV3, were selected, and we found that they all had increased affinities for the MAST2 PDZ domain, with Kd values decreasing from 1300 to 60 nM, while target selectivity was maintained. A parallel biological assay evaluating neurite extension and branching in cell cultures revealed that the NV peptides gradually improved neural activity, with the efficacies of these peptides for stimulating neurite outgrowth mirroring their affinities for MAST2-PDZ. We also show that NVs can be delivered into the cytoplasm of neurons as a gene or peptide. In summary, our findings indicate that virus-derived peptides targeted to MAST2-PDZ stimulate neurite outgrowth in several neuron types, opening up promising avenues for potentially using NVs in the management of neurodegenerative diseases. %G English %2 https://pasteur.hal.science/pasteur-02271324/document %2 https://pasteur.hal.science/pasteur-02271324/file/Article%20Khan%20et%20al%20july%202019.pdf %L pasteur-02271324 %U https://pasteur.hal.science/pasteur-02271324 %~ INSERM %~ PASTEUR %~ CNRS %~ UNIV-AMU %~ INRA %~ APHP %~ ICM %~ AGREENIUM %~ SORBONNE-UNIVERSITE %~ SORBONNE-UNIV %~ SU-MEDECINE %~ SU-MED %~ INRAE %~ SU-TI %~ ANR %~ AFMB %~ ALLIANCE-SU %~ PASTEUR_UMR3569 %~ INRAEPACA