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.
Molecular Pharmaceutics, 2018, 15 (8), pp 3356–3368, doi:10.1021/acs.molpharmaceut.8b00380, PMID: 29979597