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Investigation on hybrid molecules as powerful novel therapeutic approaches for Multiple Sclerosis and myelin- related rare diseases

19th national competition for scientific and technical research

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS): Molecular Etiology and Novel Treatments

Senior Researcher : Fernando de Castro Soubriet

Research Centre or Institution : Instituto Cajal. CSIC. Madrid.

Abstract

In these few months since the beginning of the project our, group together with the group of Dr. Valle Palomo at CIB-CSIC, has set out the following work pipelines:

Test and validate chemical protocols to synthesise peptide-compound hybrid molecules (HMs). As a proof of concept, reporter fluorophores have been added to two candidate peptides:

Our objective: efficient synthesis of a family of HMs with the ability to target the central nervous system and more specifically oligodendroglial lineage cells.
Results: two potentially selective membrane-penetrating peptides have been designed and synthesized. These have been conjugated with protein kinase inhibitors for the evaluation of their neurogenic potential in cultures of oligodendrocyte precursor cells (OPCs).
Next steps: In vitro properties of the conjugates drug-peptide such as the crossing of the blood-brain barrier will be studied together with the activity in OPCs cultures.

In cell and in vivo study of pharmacokinetics of HMs. We have treated cells and mice with these HMs in order to assess anatomical and cellular distribution:

Our objective in vivo: in this first approach, to assess HMs in terms of their pharmacokinetic properties in order to find the most efficient ones crossing the blood-brain barrier and specifically target oligondendroglial lineage cells.
Results in vivo: due to the pandemic-derived restrictions in the Animal Facilities of our institution, we could just assessed one set of mice, in this case in treatment times significatively inferior, as origin reference for pharmacokinetic time evaluation. No HMs penetration was observed in CNS.
Next steps: assessment of new mice sets with longer treatment times, with additional controls and the new HMs, synthesised with drugs.
Our objective in cell: assess the intake (endocytosis) and co-localization of our reporter fluorophores, and the effect of peptide-bound drugs in different type of brain cells.
Results: in spite of the restrictions of the Culture Service, we observed that CTB2.20 is significatively more promiscuous than CTB2.21, thus penetrating in non-target cells at submicromolar concentrations.
Next steps: continue checking of peptide-fluorophore and peptide-drugs in cell lines and OPCs primary cultures.

 

Scientific Production
 
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Communications at national conferences -
Communications at international conferences 2

 

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