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)