Identification of Novel Peptides as Potential Modulators of Aß42 Amyloidogenesis: An in silico Approach.

AIMS: Alzheimer's disease is a neurodegenerative disease for which no cure is available. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease. BACKGROUND: The proteolysis of Amyloid Precursor Protein by presenilin leads to the formation of Amyloid-beta peptides (Aß 42/40). Deposition of 42 residual Aß peptides forms fibril's structure, disrupting neuron synaptic transmission, inducing neural cell toxicity, and ultimately leading to neuron death. OBJECTIVE: Various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies to investigate their effects on Aß amyloidogenesis. METHODS: The sequence-based peptides were rationally designed and investigated for their interaction with Aß42 monomer and fibril, and their influence on the structural stability of target proteins was studied. RESULTS: Analyzed docking results suggest that the peptide YRIGY (P6) has the highest binding affinity with Aß42 fibril amongst all the synthetic peptides, and the peptide DKAPFF (P12) similarly shows a better binding with the Aß42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action. CONCLUSION: These findings indicate that both the rationally designed peptides can modulate amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils. In contrast, peptide P12 stabilizes the native structure of the Aß42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimer's disease. Experimental testing of these peptides for immunogenicity, stability in cellular conditions, toxic effects and membrane permeability can be the future research scope of this study.

Human Serum Albumin Aggregation and its Modulation Using Nanoparticles: A Review.

Amyloid fibrils are highly stable protein fibrillar aggregates believed to be involved in various neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, and prion diseases. Inhibiting the aggregation process is a potential strategy to prevent diseases caused by amyloid formation. In this regard, nanoparticles have emerged as promising candidates owing to their unique physical/chemical properties of small size, large surface area, biocompatibility, biodegradability, non-toxicity, and ease of functionalization. Human Serum Albumin (HSA) is a soluble multidomain monomeric protein that interacts with various ligands and hormones, aiding in their transport, distribution, metabolism in the circulatory system, and also plays a vital role in extracellular fluid volume stabilization. Under certain in vitro conditions, HSA has been reported to undergo conformational changes leading to fibril formation and hence acts as a suitable model for studying amyloidogenesis. In this review, we have explored the effects of various nanoparticles on HSA aggregation and their mechanism of action. The study will throw light on the mechanistic details of nanoparticle-mediated amyloid modulation, which will help in the development of effective therapeutics against amyloidosis.