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.

+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.

Tailoring the Physicochemical Properties of Antimicrobial Peptides onto a Thiazole-Based γ-Peptide Foldamer

J. Med. Chem. 2020, 63, 17, 9168–9180.

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




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,

J. Kaffy J., Berardet C., Mathieu L., Legrand B., Taverna M., Halgand F., Van Der Rest G., Maillard L. T., Ongeri S.



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;
Baptiste Legrand, Julie Aguesseau-Kondrotas, Matthieu Simon and Ludovic Maillard




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.


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


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


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

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.


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.

How are 1,2,3-triazoles accommodated in helical secondary structures?

Org Biomol Chem. 2018 May 15. doi: 10.1039/c8ob00686e

Ben Haj Salah K, Das S , Ruiz N , Andreu V , Martinez J , Wenger E , Amblard M , Didierjean C , Legrand B , Inguimbert N


1,4-Disubstituted-1,2,3-triazole (Tz) is widely used in peptides as a trans-amide bond mimic, despite having hazardous effects on the native peptide activity. The impact of amide bond substitution by Tz on peptide secondary structures is scarcely documented. We performed a Tz scan, by systematically replacing peptide bonds following the Aib residues with Tz on two model peptaibols: alamethicin F50/5 and bergofungin D, which adopt stable α- and 310 helices, respectively. We observed that the Tz insertion, whatever its position in the peptide sequences, abolished their antimicrobial activity. The structural consequences of this insertion were further investigated using CD, NMR and X-ray diffraction. Importantly, five crystal structures that were incorporated with Tz were solved, showing various degrees of alteration of the helical structures, from minor structural perturbation of the helix to partial disorder. Together, these results showed that Tz insertions impair helical secondary structures.

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.


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.

Synthesis of [1,2,4]Triazolo[4,3- a]piperazin-6-ones: An Approach to the Triazole-Fused Ketopiperazine Scaffold

Org Lett. 2018 Jun 1;20(11):3250-3254. doi: 10.1021/acs.orglett.8b01112. Epub 2018 May 15.

Ben Haj Salah K, Legrand B, Bibian M, Wenger E, Fehrentz JA, Denoyelle S.


A stereoconservative synthesis to access the triazole-fused ketopiperazine (TKP) scaffold is presented. This underexplored platform offers a wide range of structural modulations with several points of diversity and chiral centers. A series of [1,2,4]triazolo[4,3- a]piperazin-6-ones was synthesized from optically pure dipeptides. The methodology was then successfully applied to access the pyrrolo[1,2- a]triazolo[3,4- c]piperazin-6-one tricycle. Importantly, the crystal structures of representative TKPs confirmed that the configuration of the chiral centers was controlled during the synthetic route and facilitated description of the orientation of the substituents depending on their nature and position on the TKP scaffold.