Our group synthesizes stapled peptides and pseudopeptide oligomers constructed from constrained β- and γ-amino acids or dipeptide mimetics able to adopt stable and predictable helical and ribbon conformations. Due to their well-defined secondary structure and their resistance to enzyme degradation, stapled peptides and foldamers are used for various biological applications, in particular for the development of efficient vectors for drug delivery, antimicrobials, inhibitors of protein-protein interactions and the targeting of the mannose 6-phosphate receptor for non-invasive cancer therapy. Bio-inspired foldamer catalysts built on heterocyclic γ-peptide scaffolds are also currently developed.
Synthesis and structural analysis of foldamers
We synthesize and characterize various homo- and hetero-oligomers using the ABOC, ATC residues which are constrained β- and γ-building blocks respectively, and Agl-AA dipeptide mimics. Depending on the sequence, we obtained different architectures, from various helices to ribbons.
Numerous techniques, i.e. CD, FTIR and NMR spectroscopies, X-ray diffraction and DFT calculations are combined to characterize the three dimensional structure of the various oligomers.
Interaction with proteins
Stapled peptides and foldamers are currently evaluated for their ability to regulate physiological processes inhibiting protein-protein interactions, proteins aggregation in various pathological context such as cancers or Alzheimer disease as example. We also developed original glycofoldamers targeting the mannose 6-phosphate receptor overexpressed in prostate cancer cell lines and tissues.
Development of antimicrobial foldamers
A bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β-pleated sheet conformation similar to that of the natural compound. The hybrid α,γ-cyclopeptide exhibited significant reduced hemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity [1-3]. New highly selective sequences exhibiting strong antimicrobial activities are currently developed.
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The Unexpected Helical Supramolecular Assembly of a Simple Achiral Acetamide Tecton Generates Selective Water Channels
Abstract
Achiral 2-hydroxy-N-(diphenylmethyl)acetamide (HNDPA) crystallizes in the P61 chiral space group as a hydrate, building up permeable chiral crystalline helical water channels. The crystallization-driven chiral self-resolution process is highly robust, with the same air-stable crystalline form readily obtained under a variety of conditions. Interestingly, the HNDPA supramolecular helix inner pore is filled by a helical water wire. The whole edifice is mainly stabilized by robust hydrogen bonds involving the HNDPA amide bonds and CH… π interactions between the HNDPA phenyl groups. The crystalline structure shows breathing behavior, with completely reversible release and re-uptake of water inside the chiral channel under ambient conditions. Importantly, the HNDPA channel is able to transport water very efficiently and selectively under biomimetic conditions. With a permeability per channel of 3.3 million water molecules per second in large unilamellar vesicles (LUV) and total selectivity against NaCl, the HNDPA channel is a very promising functional nanomaterial for future applications.
α,β-Unsaturated γ-Peptide Foldamers
Chempluschem. 2021 Apr 1;86(4):629-645. doi: 10.1002/cplu.202100045. Online ahead of print.
Legrand B, Maillard LT
Abstract
Despite their concomitant emergence in the 1990s, γ-peptide foldamers have not developed as fast as β-peptide foldamers and to date, only a few γ-oligomer structures have been reported, and with sparse applications. Among these examples, sequences containing α,β-unsaturated γ-amino acids have recently drawn attention since the Z/E configurations of the double bond provide opposite planar restrictions leading to divergent conformational behaviors, from helix to extended structures. In this Review, we give a comprehensive overview of the developments of γ-peptide foldamers containing α,β-unsaturated γ-amino acids with examples of applications for health and catalysis, as well as materials science.
Tailoring the Physicochemical Properties of Antimicrobial Peptides onto a Thiazole-Based γ-Peptide Foldamer
J. Med. Chem. 2020, 63, 17, 9168–9180. https://doi.org/10.1021/acs.jmedchem.0c00077
Abstract
Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-based γ-peptide oligomers named ATCs as tunable scaffolds to design polycationic AMP mimetics. Knowing the side chain distribution along the backbone, we rationally designed facially amphiphilic sequences with bactericidal effect in the micromolar range. Since no hemolytic activity was detected up to 100 μM, this class of compounds has shown the potential for therapeutic development.
Helical γ-peptide foldamers as dual inhibitors of amyloid-β peptide and islet amyloid polypeptide oligomerization and fibrillization
Chem. Eur. J. 26, 14612-14622, https://doi.org/10.1002/chem.202001716
J. Kaffy J., Berardet C., Mathieu L., Legrand B., Taverna M., Halgand F., Van Der Rest G., Maillard L. T., Ongeri S.
Abstract
Type 2 diabetes (T2D) and Alzheimer’s disease (AD) belong to the 10 deadliest diseases and are sorely lacking in effective treatments. Both pathologies are part of the degenerative disorders named amyloidoses, which involve the misfolding and the aggregation of amyloid peptides, hIAPP for T2D and Aβ1‐42 for AD. While hIAPP and Aβ1‐42 inhibitors have been essentially designed to target β‐sheet‐rich structures composing the toxic amyloid oligomers and fibrils of these peptides, the strategy aiming at trapping the non‐toxic monomers in their helical native conformation has been rarely explored. We report herein the first example of helical foldamers as dual inhibitors of hIAPP and Aβ1‐42 aggregation and able to preserve the monomeric species of both amyloid peptides. A foldamer composed of 4‐amino(methyl)‐1,3‐thiazole‐5‐carboxylic acid (ATC) units, adopting a 9‐helix structure reminiscent of 310 helix, was remarkable as demonstrated by biophysical assays combining thioflavin‐T fluorescence, transmission electronic microscopy, capillary electrophoresis and mass spectrometry.
Catalytic Foldamers: When the Structure Guides the Function
Abstract
Enzymes are predominantly proteins able to effectively and selectively catalyze highly complex biochemical reactions in mild reaction conditions. Nevertheless, they are limited to the arsenal of reactions that have emerged during natural evolution in compliance with their intrinsic nature, three-dimensional structures and dynamics. They optimally work in physiological conditions for a limited range of reactions, and thus exhibit a low tolerance for solvent and temperature conditions. The de novo design of synthetic highly stable enzymes able to catalyze a broad range of chemical reactions in variable conditions is a great challenge, which requires the development of programmable and finely tunable artificial tools. Interestingly, over the last two decades, chemists developed protein secondary structure mimics to achieve some desirable features of proteins, which are able to interfere with the biological processes. Such non-natural oligomers, so called foldamers, can adopt highly stable and predictable architectures and have extensively demonstrated their attractiveness for widespread applications in fields from biomedical to material science. Foldamer science was more recently considered to provide original solutions to the de novo design of artificial enzymes. This review covers recent developments related to peptidomimetic foldamers with catalytic properties and the principles that have guided their design.
Topological Requirements for CI-M6PR-Mediated Cell Uptake
Bioconjugate Chemistry 2019 30 (10), 2533-2538 DOI: 10.1021/acs.bioconjchem.9b00590
Simon M*, Ali LMA*, El Cheikh K, Aguesseau-Kondrotas J, Godefroy A, Nguyen C, Garcia M, Morère A, Gary-Bobo M, Maillard L.
Abstract
The 300 kDa cation-independent M6P receptor (CI-MPR) mediates ligand internalization and trafficking to the endolysosomal compartments. Because of its endocytotic nature, it has been recognized as a promising class of receptors for target component delivery. Its cellular uptake involves the simultaneous binding of two protein units resulting in the formation of receptor dimers. While many multivalent glycoconjugates have been reported to date, little is known about the topological requests to induce an effective recruitment of CI-MPRs. We herein describe the synthesis and cell uptake ability of a set of highly organized glycoclusters bearing one to three saccharide units. The spatial arrangement of carbohydrate ligands is ensured by a heterocyclic γ-peptide central core.
Prospect of Thiazole-based gamma-Peptides Foldamers in Enamine Catalysis: Exploration of the Nitro-Michael Addition
Chemistry. 2019 May 28;25(30):7396-7401. doi: 10.1002/chem.201901221. Epub 2019 May 7.
Aguesseau-Kondrotas J, Simon M, Legrand B, Bantigniès JL, Kang YK, Dumitrescu D, Van der Lee A, Campagne JM, de Figueiredo RM, Maillard LT.
Abstract
As three-dimensional folding is prerequisite to biopolymer activity, complex functions may also be achieved through foldamer science. Because of the diversity of sizes, shapes and folding available with synthetic monomers, foldamer frameworks enable a numerous opportunities for designing new generations of catalysts. We herein demonstrate that heterocyclic γ-peptide scaffolds represent a versatile platform for enamine catalysis. One central feature was to determine how the catalytic activity and the transfer of chiral information might be under the control of the conformational behaviours of the oligomer.
12/10-Helix in Mixed β-Peptides Alternating Bicyclic and Acyclic β-Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability
Chemistry. 2018 Dec 12. doi: 10.1002/chem.201804404. Epub 2018 Nov 15
Simon M, Milbeo P, Liu H, André C, Wenger E, Martinez J, Amblard M, Aubert E, Legrand B, Calmès M.
Abstract
12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained β2, 3, 3 -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted β-homologated proteinogenic amino acid (l-β3 -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3 OH, CDCl3 , and [D6 ]DMSO, respectively. The stability of the hydrogen bonds forming the C10 and C12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic β-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the β3 -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.
Can Heterocyclic γ-Peptides Provide Polyfunctional Platforms for Synthetic Glycocluster Construction?
Chemistry. 2018 Aug 6;24(44):11426-11432. doi: 10.1002/chem.201802032
Simon M, Ali LMA, El Cheikh K, Aguesseau J, Gary-Bobo M, Garcia M, Morère A, Maillard LT.
Abstract
Sugars play key roles in many molecular and cellular communication processes involving a family of proteins named lectins. The low affinity associated with sugar recognition is generally counterbalanced by the multivalent nature of the interaction. While many polyglycosylated architectures have been described, only a few studies focused on the impact of topology variations of the multivalent structures on the interaction with lectin proteins. One major interest of our group concerns the design of new highly predictable and stable molecular pseudo‐peptide architectures for therapeutic applications. In such a context, we described a class of constrained heterocyclic γ‐amino acids built around a thiazole ring, named ATCs. ATC oligomers are helical molecules resulting from the formation of a highly stable C9 hydrogen‐bonding pattern. Following our program, we herein address the potential of ATC oligomers as tunable scaffolds for the development of original multivalent glycoclusters.
Selectivity Modulation and Structure of α/aza-β3 Cyclic Antimicrobial Peptides
Chemistry. 2018 Apr 20;24(23):6191-6201. doi: 10.1002/chem.201800152. Epub 2018 Mar 26.
Simon M, Laurencin M, Fleury Y, Baudy-Floc’h M, Bondon A, Legrand B.
Abstract
Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β3 -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza-β3 -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β3 residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β3 -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach.
