Rational design approaches to interfere with protein misfolding and aggregation through peptidomimetic foldamers

The aggregation of proteins into amyloid fibers is linked to more than 40 still incurable cellular and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease and type 2 diabetes. The process of amyloid formation is a main feature in cell degeneration and disease pathogenesis. Many anti-amyloid molecules have been reported over the past 25 years and most of them belong to small molecules or antibodies. However, so far only one of the anti-amyloid drug candidates, Tafamidis, which inhibits transthyretin amyloidogenesis (TTR), and an antibody, Aducanumab, which targets aggregates of beta-amyloid peptide 1- 42 (Aβ1-42), reached the clinic. Peptides are an attractive alternative to small molecules and antibodies as anti-amyloid drugs, thanks to their improved efficacy, selectivity or specificity, and potency. However, very few of them have reached the (pre) clinical stages, and so far, none of them has reached the clinic. Peptidomimetic foldamers, bio-inspired by secondary structures of amyloid proteins, provide a promising alternative to peptides because they keep the specific side chains of a peptide sequence while having new and improved biological and pharmacokinetic properties and the possibility of adopting secondary structures frequently involved in protein- protein interactions. Rational design approaches to interfere with protein misfolding and aggregation through peptidomimetic foldamers (β-strand, PPII and α-helix) are here presented. The design has been based on both self-aggregation and cross- interaction processes. These foldamers have shown a good ability in vitro to interfere with the aggregation process of Aβ1-42 and tau, especially those with a stable secondary conformation. Circular dichroism analyses on the conformational change of the amyloid protein in the presence of these foldamers revealed their ability to stabilize intermediate conformations, which could be the reason for the reduced aggregation propensity and thus toxicity. These approaches represent a practical application of peptidomimetic foldamers in therapeutics, particularly in pathologies involving abnormal protein-protein interactions. 1. N. Tonali, L. Hericks, D.C. Schröder, O. Kracker, R. Krzemieniecki, J. Kaffy, V. Le Joncour, P. Laakkonen, A. Marion, S. Ongeri, V. I. Dodero, N. Sewald; ChemPlusChem 2021, 86(6), 840. 2. L. Ciccone, C. Shi, D. Di Lorenzo, A.C. Van Baelen, N. Tonali; Molecules 2020, 25(10), 2439. 3. Shi, C.; Kaffy, J.; Ha-Duong, T.; Gallard, J.-F.; Pruvost, A.; Mabondzo, A.; Ciccone, L.; Ongeri, S.; Tonali, N.; J. Med. Chem. 2023, 66 (17), 12005–12017.

12/04/2024 Prof. Nicolo Tonali: FLUOPEPIT, BioCIS, CNRS, Université Paris Saclay,Châtenay-Malabry (France)

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