Peptide‐Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration

Abstract

Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell‐ and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti‐amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry “tools” to design, develop, and discover peptide‐based molecules as anti‐amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1) the oldest and most common strategy, based on molecular recognition elements of amyloid self‐assembly, and 2) a more recent approach, based on cross‐amyloid interactions. We discuss why peptide‐based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti‐amyloid drugs as well as valuable tools for deciphering amyloid‐mediated cell damage and its link to disease pathogenesis.

Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

“…Exploitation of the principle of self-recognition has proven fruitful for the design of amyloid formation inhibitors. 47,48 Here, we showed that modication of aS by introduction of a hairpin in a critical N-terminal region results in an inhibitor of bril elongation, whose efficiency is strongly dependent on the precise position of the hairpin. Our data demonstrates that the efficiency of such bril-end blocking inhibitors may be dramatically enhanced by linkage to WT monomer, as WT monomer is capable of stabilizing the blocked bril-end state.…”

“…It was earlier observed that subtly modied fragments of an amyloidogenic protein can be highly inhibitory. 47,48 CC48, as well as aS, is intrinsically disordered in solution and as such the b-hairpin region is available for potential binding and interfering with bril-ends. 26 To test if the observed inhibition could be explained solely by the b-hairpin region of CC48, we performed elongation experiments in the presence of synthetic peptides composed of the bhairpin region of CC48 as well as the WT sequence ( Fig.…”

Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease

“…Notwithstanding, the mechanisms by which IAPP contributes to AD pathology are still unclear and deserve further enquiry. It is known that IAPP and Aβ interact with each other and that IAPP promotes Aβ aggregation in a seeding-like manner, leading to the formation of cross-seeded oligomers (Andreetto et al, 2010;Rezaei-Ghaleh et al, 2011;Yan et al, 2014;Hu et al, 2015;Bakou et al, 2017;Moreno-Gonzalez et al, 2017;Ge et al, 2018;Armiento et al, 2019). Interestingly, an aggregation blocker mimicking IAPP has been proven to work against Aβ (Yan et al, 2007).…”

New Human Islet Amyloid Polypeptide Fragments Susceptible to Aggregation

“…The 23-27 H-FGAIL-OH amylin fragment, which is the known amyloidogenic hIAPP core, was used as a model object and also as an internal control. [44] Tests on the amyloidogenic properties of the amylin fragments were carried out using Congo Red (CR) (Figures 2 and 3) and Thioflavin T assays (Figure 4), as well as microscopic techniques for peptide aggregates ( Figure 5). [45][46][47][48][49][50] The use of three independent methods avoided potential problems resulting from the fact that methods used to study weak interactions, including self-organization processes, have a high risk of false results.…”