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Calmidazolium Chloride and Its Complex with Serum Albumin Prevent Huntingtin Exon1 Aggregation

Journal Type:  Journal Paper
Journal:  Molecular Pharmaceutics, 2018, Aug 6, 15 (8), pp 3356–3368, doi:10.1021/acs.molpharmaceut.8b00380
Pubmed:  29979597
Impact Factor:  4.556
Date of Acceptance:   6 Jul 2018

Huntington’s disease (HD) is a genetic disorder caused by a CAG expansion mutation in Huntingtin gene leading to polyglutamine (polyQ) expansion in the N-terminus side of Huntingtin (Httex1) protein. Neurodegeneration in HD is linked to aggregates formed by Httex1 bearing expanded polyQ. Initiation and elongation steps of Httex1 aggregation are potential target steps for the discovery of therapeutic molecules, for yet untreatable and cruel, HD. Here we report Httex1 aggregation inhibition by calmidazolium chloride (CLC) by acting on the initial aggregation event. Being hydrophobic, CLC was adsorbed to the vial surface and could not sustain inhibition effect for longer duration. Usage of bovine serum albumin (BSA) prevented its adsorption by forming BSA-CLC complex. This complex showed improved Httex1 aggregation inhibition by interacting with the aggregation initiator, NT17 part of Httex1. Further, a biocompatible CLC loaded BSA nanoparticles were made which reduced the polyQ aggregates in HD-150Q cells.