PT  - JOURNAL ARTICLE
AU  - Bikash R. Sahoo
AU  - Takuya Genjo
AU  - Andrea K. Stoddard
AU  - Kazuma Yasuhara
AU  - Carol A. Fierke
AU  - Ayyalusamy Ramamoorthy
TI  - Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation
AID  - 10.1101/401687
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 401687
4099  - http://biorxiv.org/content/early/2018/08/27/401687.short
4100  - http://biorxiv.org/content/early/2018/08/27/401687.full
AB  - In human, amyloid-beta (Aβ) and islet amyloid polypeptide (hIAPP) aggregations are linked to Alzheimer’s disease and Type-2 Diabetes, respectively. There is significant interest in better understanding the aggregation process by using chemical tools. Here, we show the ability of a cationic polymethacrylate-copolymer (PMAQA) to quickly induce β-hairpin structure and promote fibrillation in Aβ40, and to constrain the conformational plasticity of hIAPP for several days and inhibit its aggregation at sub-micromolar concentrations. NMR experiments and atomistic molecular dynamics simulations reveal that PMAQA electrostatically interacts with Aβ40’s Glu22 and Asp23 followed by β-sheet induction while it binds strongly to the closest proximity of amyloid core domain (NFGAIL) of hIAPP and restrain its structural rearrangement. This study provides a valuable approach to develop polymer-based anti-amyloid inhibitors that may diminish the population of intermediates of Aβ40 or hIAPP.