IDENTIFICATION OF FIRST-IN-CLASS INHIBITORS OF KALLIKREIN-RELATED PEPTIDASE 6 THAT PROMOTE OLIGODENDROCYTE DIFFERENTIATION
In: ISSN: 0022-2623, 2021
Online
academicJournal
Zugriff:
International audience ; Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory and cognitive impairments. KLK6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelinproducing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of KLK6 proteolytic network encompassing KLK1 and plasmin that also participate to the development of MS physiopathology. Moreover, hits were found non-cytotoxic on primary cultures of murine neurons and oligodendrocyte precursors (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.
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IDENTIFICATION OF FIRST-IN-CLASS INHIBITORS OF KALLIKREIN-RELATED PEPTIDASE 6 THAT PROMOTE OLIGODENDROCYTE DIFFERENTIATION
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Autor/in / Beteiligte Person: | Aït Amiri, Sabrina ; Deboux, Cyrille ; Soualmia, Feryel ; Chaaya, Nancy ; Louet, Maxime ; Duplus, Eric ; Betuing, Sandrine ; Nait Oumesmar, Brahim ; Masurier, Nicolas ; El Amri, Chahrazade ; Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Institut du Cerveau = Paris Brain Institute (ICM) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Institut des Biomolécules Max Mousseron Pôle Chimie Balard (IBMM) ; Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM) ; Université de Montpellier (UM) ; Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM) ; Neuroscience Paris Seine (NPS) |
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Zeitschrift: | ISSN: 0022-2623, 2021 |
Veröffentlichung: | HAL CCSD ; American Chemical Society, 2021 |
Medientyp: | academicJournal |
DOI: | 10.1021/acs.jmedchem.0c02175 |
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