The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

Abstract

In recent years, due to the aging of the population and the development of diagnostic medicine, the number of identified diseases associated with the accumulation of amyloid proteins has increased. Some of these proteins are known to cause a number of degenerative diseases in humans, such as amyloid-beta (Aβ) in Alzheimer’s disease (AD), α-synuclein in Parkinson’s disease (PD), and insulin and its analogues in insulin-derived amyloidosis. In this regard, it is important to develop strategies for the search and development of effective inhibitors of amyloid formation. Many studies have been carried out aimed at elucidating the mechanisms of amyloid aggregation of proteins and peptides. This review focuses on three amyloidogenic peptides and proteins—Aβ, α-synuclein, and insulin—for which we will consider amyloid fibril formation mechanisms and analyze existing and prospective strategies for the development of effective and non-toxic inhibitors of amyloid formation. The development of non-toxic inhibitors of amyloid will allow them to be used more effectively for the treatment of diseases associated with amyloid.

Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

“…8,9 They rely primarily on the design of small molecules or antibodies that bind to monomeric or aggregated protein species, thereby making the substrate unavailable for conversion 10 and/or sterically interfering with the aggregation process. 9,[11][12][13] Traditional small molecule drugs and protein-based therapeutics have made good contributions, yet their limitations in terms of selectivity, stability, and bioavailability, 14,15 as well as their repeated failure in clinical trials 16,17 have inspired the search for alternative therapeutic approaches. Among these, peptides and particularly cyclic peptides are attracting considerable attention due to their unique structural properties and diverse biological activities.…”

“…[3][4][5][6][7] Various approaches have been developed to interfere with the accumulation processes by stabilizing or eliminating specific monomeric or aggregated forms of the responsible polypeptides. 8,9 They rely primarily on the design of small molecules or antibodies that bind to monomeric or aggregated protein species, thereby making the substrate unavailable for conversion 10 and/or sterically interfering with the aggregation process. 9,[11][12][13] Traditional small molecule drugs and protein-based therapeutics have made good contributions, yet their limitations in terms of selectivity, stability, and bioavailability, 14,15 as well as their repeated failure in clinical trials 16,17 have inspired the search for alternative therapeutic approaches.…”

Characterizing fibril morphological changes by spirooxindoles for neurodegenerative disease application

“…Research has been done on many different variants of natural products which have shown increasing potential in inhibiting the formation of amyloid fibrils in vitro. 20 The most widely studied natural products which have been documented include epigallocatechin gallate (EGCG), 21 resveratrol 22 and curcumin. 23 These small polyphenolic compounds show remarkable inhibition of the formation of fibrillar assemblies in vitro.…”