Discovery of arginine ethyl ester as polyglutamine aggregation inhibitor: Conformational transitioning of huntingtin N-terminus augments aggregation suppression.

Huntington disease (HD) is a genetic disorder caused by CAG expansion mutation in Huntingtin gene leading to polyglutamine (PolyQ) expansion in the N-terminus part of Huntingtin (Httex1). Expanded PolyQ, through complex aggregation pathway forms aggregate in neurons and present a potential therapeutic target. Here we show Httex1 aggregation suppression by arginine and arginine ethyl ester (AEE) , as well as in yeast and mammalian cell models of HD, bearing expanded polyQ. These molecules also rescue locomotion dysfunction in HD model. Both molecules alter the hydrogen bonding network of polyQ to enhance its aqueous solubility and delay aggregation. AEE shows direct binding with NT part of Httex1 to induce structural changes to impart an enhanced inhibitory effect. This study provides a platform for the development of better arginine based therapeutic molecule against polyQ-rich Httex1 aggregation.