posted on 2021-05-05, 13:38authored bySabrina Aït Amiri, Cyrille Deboux, Feryel Soualmia, Nancy Chaaya, Maxime Louet, Eric Duplus, Sandrine Betuing, Brahim Nait Oumesmar, Nicolas Masurier, Chahrazade El Amri
Multiple
sclerosis (MS) is an autoimmune demyelinating disease
of the central nervous system (CNS) that causes severe motor, sensory,
and cognitive impairments. Kallikrein-related peptidase (KLK)6 is
the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes,
the myelin-producing 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 the KLK6 proteolytic network encompassing
KLK1 and plasmin that also participate in the development of MS physiopathology.
Moreover, hits were found noncytotoxic on primary cultures of murine
neurons and oligodendrocyte precursor cells (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.