Baptiste Legrand

Baptiste legrand
Research Engineer, University of Montpellier (UM)

Baptiste is a Research Engineer at the Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier. He received his PhD in biology and life sciences from the University of Rennes 1 in 2009. Then, he moved for a two years post-doctoral fellowship at the Laboratory of Macromolecular Chemistry and Physics (LCPM, Nancy) working on the characterization of foldamers structures combining various techniques (NMR, CD and FTIR spectroscopies, and Molecular Dynamics) and then he joined the IBMM in 2012. His research is mainly devoted on the rational design of peptidomimetics and organized molecular architectures to modulate biological processes focusing on the structural aspects. He is in charge of the conformational studies of various chemical tools developed at the IBMM but also collaborates with other groups.

Contact:
baptiste.legrand_at_umontpellier.fr
+33 411 75 96 06

5 major publications :

Legrand B, André C, Moulat L, Didierjean C, Hermet P, Bantignies JL, Martinez J, Amblard M, Calmès M. 12/14/14-Helix Formation in 2:1 α/β-Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints. Chemistry. 2016. 16;22(34):11986-90.

Martin V, Legrand B, Vezenkov LL, Subra G, Calmès M, Bantignies J.L, Martinez J,  Amblard M. Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction. Angew. Chem. Int. Ed. 2015. 16;54(47):13966-70.

Legrand B, André C, Moulat L, Wenger E, Didierjean C, Aubert E, Averlant-Petit MC, Martinez J, Calmes M, Amblard M. Unprecedented chain-length-dependent conformational conversion between 11/9 and 18/16 helix in α/β-hybrid peptides. Angew Chem Int Ed. 2014. 53(48):13131-5.

Mathieu L, Legrand B, Deng C, Vezenkov L, Wenger E, Didierjean C, Amblard M, Averlant-Petit MC, Masurier N, Lisowski V, Martinez J, Maillard LT. Helical oligomers of thiazole-based γ-amino acids: synthesis and structural studies. Angew Chem Int Ed. 2013. 3;52(23):6006-10.

Legrand B, André C, Wenger E, Didierjean C, Averlant-Petit MC, Martinez J, Calmes M, Amblard M. Robust helix formation in a new family of oligoureas based on a constrained bicyclic building block. Angew Chem Int Ed. 2012. 51(45):11267-70.

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.

1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid and Derivatives As Chiral Constrained Bridged Scaffolds for Foldamers and Chiral Catalysts

Acc Chem Res. 2021 Feb 2;54(3):685-696. doi: 10.1021/acs.accounts.0c00680. Epub 2021 Jan 19.

Milbeo P, Martinez J, Amblard M, Calmès M, Legrand B

 

Abstract

The improvement of molecular diversity is one of the major concerns of chemists since the continuous development of original synthetic molecules provides unique scaffolds usable in organic and bioorganic chemistry. The challenge is to develop versatile platforms with highly controlled chemical three-dimensional space thanks to controlled chirality and conformational restraints. In this respect, cyclic β-amino acids are of great interest with applications in various fields of chemistry. In addition to their intrinsic biological properties, they are important precursors for the synthesis of new generations of bioactive compounds such as antibiotics, enzyme inhibitors, and antitumor agents. They have also been involved in asymmetric synthesis as efficient organo-catalysts in their free form and as derivatives. Finally, constrained cyclic β-amino acids have been incorporated into oligomers to successfully stabilize original structures in foldamer science with recent successes in health, material science, and catalysis. Over the last ∼10 years, we focused on bicyclic β-amino acids possessing a bicyclo[2.2.2]octane structure. This latter is a structural key element in numerous families of biologically active natural and synthetic products and is an interesting template for asymmetric synthesis. Nonetheless, reported studies on bicyclic carbo-bridged compounds are rather limited compared to those on bicyclic-fused and heterobridged derivatives. In this Account, we particularly focused on the synthesis and applications of the 1-aminobicyclo[2.2.2]octane-2-carboxylic acid, named, ABOC, and its derivatives. This highly constrained bicyclic β-amino acid, with a sterically hindered bridgehead primary amine and an endocyclic chiral center, displays drastically reduced conformational freedom. In addition, its high bulkiness strongly impacts the spatial orientation of the appended functionalities and the conformation of adjacent building blocks. Thus, we have first expanded a fundamental synthetic work by a wide ranging study in the field of foldamers, in the design of various stable peptide/peptidomimetic helical structures incorporating the ABOC residue (11/9-, 18/16-, 12/14/14-, and 12/10-helices). In addition, such bicyclic residue was fully compatible with and stabilized the canonical oligourea helix, whereas very few cyclic β-amino acids have been incorporated into oligoureas. In addition, we have pursued with the synthesis of some ABOC derivatives, in particular the 1,2-diaminobicyclo[2.2.2]octane chiral diamine, named DABO, and its investigation in chiral catalytic systems. Covalent organo-catalysis of the aldol reaction using ABOC-containing tripeptide catalysts provided a range of aldol products with high enantioselectivity. Moreover, the double reductive condensation of DABO with various aldehydes allowed the building of new chiral ligands that proved their efficiency in the copper-catalyzed asymmetric Henry reaction.

Potent Lys Patch-Containing Stapled Peptides Targeting PCSK9

J Med Chem. 2021 Aug 12;64(15):10834-10848. doi: 10.1021/acs.jmedchem.0c02051. Epub 2021 Jul 15.

Bourbiaux K, Legrand B, Verdié P, Mallart S, Manette G, Minoletti C, Stepp JD, Prigent P, Le Bail JC

 

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as a regulator of low-density lipoprotein receptor (LDLR), plays a major role in cardiovascular diseases (CVD). Recently, Pep2-8, a small peptide with discrete three-dimensional structure, was found to inhibit the PCSK9/LDLR interaction. In this paper, we describe the modification of this peptide using stapled peptide and SIP technologies. Their combination yielded potent compounds such as 18 that potently inhibited the binding of PCSK9 to LDLR (KD = 6 ± 1 nM) and restored in vitro LDL uptake by HepG2 cells in the presence of PCSK9 (EC50 = 175 ± 40 nM). The three-dimensional structures of key peptides were extensively studied by circular dichroism and nuclear magnetic resonance, and molecular dynamics simulations allowed us to compare their binding mode to tentatively rationalize structure-activity relationships (SAR).

Hydrocarbon-Stapled Peptide Based-Nanoparticles for siRNA Delivery.

Nanomaterials (Basel). 2020 Nov 25;10(12):2334. doi: 10.3390/nano10122334

Simon M, Laroui N, Heyraud M, Laconde G, Ali LMA, Bourbiaux K, Subra G, Vezenkov LL, Legrand B, Amblard M, Bettache N.

 

Abstract

Small interfering RNAs (siRNAs) are promising molecules for developing new therapies based on gene silencing; however, their delivery into cells remains an issue. In this study, we took advantage of stapled peptide technology that has emerged as a valuable strategy to render natural peptides more structured, resistant to protease degradation and more bioavailable, to develop short carriers for siRNA delivery. From the pool of stapled peptides that we have designed and synthesized, we identified non-toxic vectors that were able to efficiently encapsulate siRNA, transport them into the cell and induce gene silencing. Remarkably, the most efficient stapled peptide (JMV6582), is composed of only eight amino-acids and contains only two cationic charges.

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

Clément BonnelBaptiste Legrand Matthieu SimonMargaux ClaviéAgnès Masnou  Estelle Jumas-BilakYoung Kee KangPatricia Licznar-Fajardo, Ludovic T Maillard and Nicolas Masurier

 

 

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

Catalysts 2020, 10(6), 700; https://doi.org/10.3390/catal10060700
Baptiste Legrand, Julie Aguesseau-Kondrotas, Matthieu Simon and Ludovic Maillard

 

 

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.

Self-mineralization and assembly of a bis-silylated Phe–Phe pseudodipeptide to a structured bioorganic–inorganic material

Mater. Horiz., 2019, 6, 2040-2046   doi: 10.1039/C9MH00580C

Jebors S, Valot L, Echalier C, Legrand L, Mikhaleff R,Van Der Lee A, Arenal R, Dumy P, Amblard M, Martinez J, Mehdi A and Subra G.

Abstract

Self-mineralization of a trialkoxysilyl hybrid peptide yields in a single step a nanostructured hybrid material. A bis-silylated pseudodipeptide inspired from the Phe–Phe dipeptide was used to program the assembly by sol–gel polymerization under heterogeneous conditions, in water at pH 1.5 without any structure-directing agent. A mechanism deciphering the hybrid material assembly was proposed thanks to 1H NMR spectroscopy. First, water-insoluble hybrid building blocks were hydrolysed into their soluble silanol counterparts. Then, these transitional species, thanks to hydrogen bonding and π–π stacking, self-assembled in solution. Last, the proximity of the silanol moieties favoured their polycondensation into growing siloxane oligomers, which spontaneously precipitated to produce an ordered hybrid material.

The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides

Int J Mol Sci. 2019 Feb 26;20(5). pii: E1021. doi: 10.3390/ijms20051021

Kebe NM, Samanta K, Singh P, Lai-Kee-Him J, Apicella V, Payrot N, Lauraire N, Legrand B, Lisowski V, Mbang-Benet DE, Pages M, Bastien P, Kajava AV, Bron P, Hernandez JF, Coux O

Abstract

HslVU is an ATP-dependent proteolytic complex present in certain bacteria and in the mitochondrion of some primordial eukaryotes, including deadly parasites such as Leishmania. It is formed by the dodecameric protease HslV and the hexameric ATPase HslU, which binds via the C-terminal end of its subunits to HslV and activates it by a yet unclear allosteric mechanism. We undertook the characterization of HslV from Leishmania major (LmHslV), a trypanosomatid that expresses two isoforms for HslU, LmHslU1 and LmHslU2. Using a novel and sensitive peptide substrate, we found that LmHslV can be activated by peptides derived from the C-termini of both LmHslU1 and LmHslU2. Truncations, Ala- and D-scans of the C-terminal dodecapeptide of LmHslU2 (LmC12-U2) showed that five out of the six C-terminal residues of LmHslU2 are essential for binding to and activating HslV. Peptide cyclisation with a lactam bridge allowed shortening of the peptide without loss of potency. Finally, we found that dodecapeptides derived from HslU of other parasites and bacteria are able to activate LmHslV with similar or even higher efficiency. Importantly, using electron microscopy approaches, we observed that the activation of LmHslV was accompanied by a large conformational remodeling, which represents a yet unidentified layer of control of HslV activation.

Stapled peptide targeting the CDK4/Cyclin D interface combined with Abemaciclib inhibits KRAS mutant lung cancer growth

Theranostics 2020; 10(5):2008-2028. doi:10.7150/thno.40971

Bouclier C*, Simon M*, Laconde G, Pellerano M, Diot S, Lantuejoul S, Busser B, Vanwonterghem L, Vollaire J, Josserand V, Legrand B, Coll JL, Amblard M, Hurbin A#, Morris MC#

* & # These authors contributed equally

Abstract

CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS-mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy.

Methods: As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1.

Results: We have validated a positive correlation between CDK4/cyclin D level and KRAS mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib.

Conclusion: The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.

Keywords: CDK4, Stapled Peptide, Inhibitor, Lung cancer (NSCLC), KRAS mutation