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2019-03-08 - Colloque/Présentation - poster - Anglais - page(s)

Derenne Aline , Kouakou Carole, Belayew Alexandra , Decleves Anne-Emilie , Tassin Alexandra , Burtea Carmen , Coppée Frédérique , "Development of peptides for specific skeletal muscle targeted drug delivery" in 2019 Advances in Skeletal Muscle Biology in Health and Disease, University of Florida, usa, 2019

  • Codes CREF : Biologie moléculaire (DI3111)
  • Unités de recherche UMONS : Biochimie métabolique et moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) DEVELOPMENT OF PEPTIDES FOR SPECIFIC SKELETAL MUSCLE-TARGETED DRUG DELIVERY Authors: A. Derenne, C. Kouakou, A. Belayew, A-E. Declèves, A. Tassin, C. Burtea, F. Coppée. In therapeutic approaches for Duchenne Muscular Dystrophy (DMD) or Facioscapulohumeral muscular dystrophy (FSHD) chemically-modified antisense oligonucleotides (ASOs), were developed to either alter splicing and restore expression of a functional dystrophin or inhibit expression of toxic DUX4 protein via the specific targeting of their respective mRNAs. Some of the splicing interfering ASOs are evaluated in clinical trials for DMD, and one of them (Eteplirsen) has been granted conditional approval by the FDA. However, the European Medicines Agency did not approve Eteplirsen mostly because of the very low amount of dystrophin restored in patient muscles. A major issue in further clinical development of these ASOs is their efficient and musclespecific uptake following systemic administration. Muscle targeting is required in order to achieve therapeutic efficacy and reduce toxicity/off-target effects. In order to select short peptides that could efficiently be internalized in muscle cells, we screened a peptide phage display library with human myotubes. We identified two peptides that were not taken up by cells of another type and are further investigated. In another approach, we performed analyses in silico to select a fragment of a molecule previously shown to be specifically internalized in muscle cells. That molecule fragment was used to screen a phage displayed peptide library and 14 promising candidates were isolated. Three peptide candidates were selected with Kd values ranging from 8x10-10 to 5.5x10-9 M. Among these, 1 peptide showed an excellent in vitro affinity, while binding modelisation in silico using ChemSketch and MarvinSketch software and HPEPDOCK bioinformatics server showed an optimal docking between this peptide and the targeted molecule fragment. The next step will be the evaluation of these peptides in vivo.