HEXOKINASE-DERIVED PEPTIDES AND THERAPEUTICAL USES THEREOF

    公开(公告)号:US20240228987A1

    公开(公告)日:2024-07-11

    申请号:US18563078

    申请日:2022-05-25

    IPC分类号: C12N9/12 A61K38/00 A61P25/28

    摘要: The inventors previously demonstrated that mitochondrial VDAC1 directly induces Schwann cell demyelination via MAPK and c-jun activation after sciatic nerve injury and diabetic neuropathy and CMT1A. They found that reduction of mitochondrial calcium release by VDAC1 blocking strongly reduces the number of demyelinating Schwann cell in vivo and improve nerve conduction and neuromuscular activity in diabetic, Guillain-Barre syndrome and Charcot-Marie Tooth disease models. Herein, the inventors precisely map the binding region of the N-terminal HK-1 helix through an ala scan completed by a deletion study. Furthermore, they optimized the HK-derived peptide through stabilization of the helix by replacement of non-essential amino acids by the a-aminoisobutyric acid (Aib) known as a helix inducer. Additionally, they described an in-house cellular screening assay based on the ability of MJ to detach HK from VDAC that allows to determine the peptide potency. Overall, their data confirm that N-terminal HK derived peptides acting on VDAC are promising tools for the study of the demyelination process. Thus, the present invention refers to optimized HK-derived peptide and its use for treating peripheral demyelinating disease, myocardium diseases10 11, cancer12,13-15, diabetes14 14-16, lupus-like diseases17, non-alcoholic fatty liver disease24,25, chemoinduced neuropathy9 Alzheimer disease18 19, Parkinson disease20, Huntington disease21, ALS22,23 and more generally all neurodegenerative diseases linked to a protein aggregation28.