Laurent Gavara

Laurent Gavara
associate professor, ENSM

Laurent Gavara completed his M. Sci. in 2005 in Montpellier and pursued his graduate studies under the supervision of Pr. Jean-Pierre Hénichart and Pr. Benoit Rigo at the University of Lille, where he received his Ph.D. in 2008. He conducted a first postdoctoral work for 2 years in Clermont-Ferrand in the Pascal Moreau group and then moved to a second postdoctoral position for 1 year in Fort Worth, US, with the Pr. Jean-Luc Montchamp. In 2012, he joined the group of Muriel Amblard at the faculty of pharmacy of Montpellier as research fellow. One year later, he reached an associate professor position in the same group. His research interests are focused on the design and the synthesis of small heterocyclic molecules. He is currently working to fight the bacterial resistance thank to the inhibition of key bacterial enzymes.


+33 (0)4 48 79 21 80

5 major publications :

L. Gavara, F. Verdirosa, L. Sevaille, A. Legru, G. Corsica, L. Nauton, P. Sandra Mercuri, F. Sannio, F. De Luca, M. Hadjadj, G. Cerboni, Y. Vo Hoang, P. Licznar-Fajardo, M. Galleni, J.-D. Docquier, J.-F. Hernandez, 1,2,4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors. Bioorg. Med. Chem. 2022, 72, 116964.

F. Verdirosa, L. Gavara, L. Sevaille, G. Tassone, G. Corsica, A. Legru, G. Feller, G. Chelini, P. Sandra Mercuri, S. Tanfoni, F. Sannio, M. Benvenuti, G. Cerboni, F. De Luca, E. Bouajila, Y. Vo Hoang, P. Licznar-Fajardo, M. Galleni, C. Pozzi, S. Mangani, J.-D. Docquier, J.-F. Hernandez, 1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors. ChemMedChem 2022, e202100699.

L. Gavara, A. Legru, F. Verdirosa, L. Sevaille, L. Nauton, G. Corsica, P. Sandra Mercuri, F. Sannio, G. Feller, R. Coulon, F. De Luca, G. Cerboni, S. Tanfoni, G. Chelini, M. Galleni, J.-D. Docquier, J.-F. Hernandez, 4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors. Bioorg. Chem. 2021, 113, 105024.

A. Legru, F. Verdirosa, J.-F. Hernandez, G. Tassone, F. Sannio, M. Benvenuti, P.-A. Conde, G., C. A. Thomas, M. W. Crowder, M. Dillenberger, K. Becker, C. Pozzi, S. Mangani, J.-D. Docquier, L. Gavara, 1,2,4- riazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-b-lactamase inhibitors with re-sensitization activity. Eur. J. Med. Chem. 2021, 226, 113873.

L. Gavara, L. Sevaille, F. De Luca, P. Mercuri, C. Bebrone, G. Feller, A. Legru, G. Cerboni, S. Tanfoni, D. Baud, G. Cutolo, B. Bestgen, G. Chelini, F. Verdirosa, F. Sannio, C. Pozzi, M. Benvenuti, K. Kwapien, M. Fischer, K. Becker, J.-M. Frère, S. Mangani, N. Gresh, D. Berthomieu, M. Galleni, J.-D. Docquier, J.-F. Hernandez, 4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors. Eur. J. Med. Chem. 2020, 208, 112720.

Structure and dynamics of G protein-coupled receptor-bound ghrelin reveal the critical role of the octanoyl chain

Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17525-17530. doi: 10.1073/pnas.1905105116. Epub 2019 Aug 15

Ferré G, Louet M, Saurel O, Delort B, Czaplicki G, M’Kadmi C, Damian M, Renault P, Cantel S, Gavara L, Demange P, Marie J, Fehrentz JA, Floquet N, Milon A, Banères JL.


Ghrelin plays a central role in controlling major biological processes. As for other G protein-coupled receptor (GPCR) peptide agonists, the structure and dynamics of ghrelin bound to its receptor remain obscure. Using a combination of solution-state NMR and molecular modeling, we demonstrate that binding to the growth hormone secretagogue receptor is accompanied by a conformational change in ghrelin that structures its central region, involving the formation of a well-defined hydrophobic core. By comparing its acylated and nonacylated forms, we conclude that the ghrelin octanoyl chain is essential to form the hydrophobic core and promote access of ghrelin to the receptor ligand-binding pocket. The combination of coarse-grained molecular dynamics studies and NMR should prove useful in improving our mechanistic understanding of the complex conformational space explored by a natural peptide agonist when binding to its GPCR. Such information should also facilitate the design of new ghrelin receptor-selective drugs.

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases

ChemMedChem 2017 Jun 21;12(12):972-985. doi: 10.1002/cmdc.201700186. Epub 2017 Jun 12.

Sevaille L, Gavara L, Bebrone C, De Luca F, Nauton L, Achard M, Mercuri P, Tanfoni S, Borgianni L, Guyon C, Lonjon P, Turan-Zitouni G, Dzieciolowski J, Becker K, Bénard L, Condon C, Maillard L, Martinez J, Frère JM, Dideberg O, Galleni M, Docquier JD, Hernandez JF.


Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.

Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex

Proceedings of the National Academy of Sciences of the United States of America, 2015, Volume: 112, Issue: 5, Pages: 1601-1606, DOI: 10.1073/pnas.1414618112

M. Damian, S. Mary, M. Maingot, C. M’Kadmi, D. Gagne, J.-P. Leyris,  S. Denoyelle, G. Gaibelet, L. Gavara, M. Costa, D. Perahia, E. Trinquet,  B. Mouillac, S. Galandrin, C. Gales, J.-A. Fehrentz, N. Floquet, J. Martinez,  J. Marie, J.-L. Baneres


How G protein-coupled receptor conformational dynamics control G protein coupling to trigger signaling is a key but still open question.  We addressed this question with a model system composed of the purified ghrelin receptor GHS-R1a assembled into lipid disks.  Combining receptor labeling through genetic incorporation of unnatural amino acids, lanthanide resonance energy transfer, and normal mode analyses, we directly demonstrate the occurrence of two distinct receptor:Gq assemblies with different geometries whose relative populations parallel the activation state of the receptor.  The first of these assemblies is a preassembled complex with the receptor in its basal conformation.  This complex is specific of Gq and is not obsd. with Gi.  The second one is an active assembly in which the receptor in its active conformation triggers G protein activation.  The active complex is present even in the absence of agonist, in a direct relationship with the high constitutive activity of the ghrelin receptor.  These data provide direct evidence of a mechanism for ghrelin receptor-mediated Gq signaling in which transition of the receptor from an inactive to an active conformation is accompanied by a rearrangement of a preassembled receptor:G protein complex, ultimately leading to G protein activation and signaling.

Ghrelin Receptor Ligands: Design and Synthesis of Pseudopeptides and Peptidomimetics

Current Chemical Biology, 2013, Volume: 7, Issue: 3, Pages: 254-270, , DOI: 10.2174/2212796807999131128125920

A. Moulin, L. Brunel, P. Verdie, L. Gavara, J. Martinez, J-A. Fehrentz


A review.  Mainly synthesized in the stomach, ghrelin is a peptide hormone which stimulates growth hormone secretion and appetite, thus promoting food intake and body-wt. gain.  Historically, researchers started to work on the discovery of ghrelin receptor ligands several years before the discovery of the ghrelin receptor and the hormone itself.  Indeed peptides able to stimulate growth hormone secretion (growth hormone releasing peptides, GHRPs) were found while the mechanism of action and the target receptor were still unknown.  Non peptidic agonists were then described (growth hormone secretagogues, GHSs) and the receptor (GHS-R1a) identified in 1996.  Three years later, the natural ligand of this receptor (ghrelin) was isolated from stomach and its chem. synthesis allowed to show the physiol. role of ghrelin in energy balance.  In this review, we present some pseudopeptide and peptidomimetic approaches used by researchers for the design of ghrelin receptor ligands.  We will start by the pioneering work of Bowers et al. on enkephalin analogs, which was the starting point for the development of an impressive no. of compds., by several of the major worldwide pharma companies.  We will also describe the work achieved starting from a substance P deriv., which was one of the first peptides identified as an antagonist of the newly discovered ghrelin receptor.  Then we will review the structure activity relationship study starting from the peptide ghrelin, which started with the discovery of this peptide in 1999.  We will also focus on a more recent work based on macrocyclic peptidic analogs for the development of ghrelin receptor ligands.