Exploring Potential of Rationally Designed Short-Synthetic Peptides as Anti-Amyloid Drug Candidates

Abstract

Misfolded and natively disordered globular proteins have a tendency to aggregate together to form fibrous, proteinaceous deposits referred to as amyloid fibrils. Formation and deposition of such insoluble fibrils are the hallmarks of a broad group of diseases known as amyloidosis, such as Amyloid-Beta (Aβ) in Alzheimer’s disease (AD), human Islet Amyloid Polypeptide (hIAPP, amylin) in type 2 diabetes, α-synuclein (α-syn) in Parkinson’s disease (PD) and so on. The fact that these proteins do not share any significant sequence or structural homology in their native states makes therapy quite challenging. Hotspot regions, known as aggregation-prone regions (APR), within the sequence of the amyloidogenic protein/peptides, are the nucleation point upon which fibril progression takes place. In the current study, we have meticulously designed synthetic hexapeptides based on the APR sequence of hen egg-white lysozyme (HEWL, a model amyloidogenic protein) referred to as SqPs (Sequence-based Peptides) and explored their antiamyloidogenic potency on in-vitro amyloid formation of HEWL at acidic pH and physiological pH. Notably, SqP1, amongst the others, exhibited a remarkable lysozyme amyloid inhibition rate of over 70% and ~50% at pH 2.2 and pH 7.5. Further, SqP1 was modified by incorporating aspartate amino acid residue to impart net charge to the peptide which is denoted as SqP4. SqP4, showed strong affinity towards the monomeric HEWL leading to the stabilization of the monomeric form and restriction in the unfolding process of monomeric HEWL. Interestingly, as the conditions chosen for conducting this study are different (acidic and neutral), the SqP4 displayed a protonation-state-dependent anti-amyloidogenic propensity against HEWL amyloid formation. Thus, the insights gained from this study can be further utilized to increase the efficacy of anti-amyloidogenic synthetic peptide inhibitors and aid in the development of synthetic peptides as therapeutics against other amyloid-related diseases such as Parkinson’s disease, Alzheimer’s disease, type II diabetes, etc.