Author: Lubomir Vezenkov

Merlion Grant : collaboration between peptide team and NTU in tissue engineering

Thanks to a Merlion grant, Gilles and Laurine spent 2 weeks in Singapore, in Pr. Sing Yian Chew’s lab at the School of Chemical and Biomedical Engineering, Nanyang Technological University. This trip was an opportunity to implant sol-gel based hydrogel scaffolds (with a collagen-like peptide) into rats to assess their ability to repair spinal cord injury.

SÉBASTIEN ESTARAN

Sébastien Estran

sébastien Estaran

Chemical engineer, CNRS

Sébastien ESTARAN graduated from a DESS in Structural Biology, obtained at the University of Montpellier in 2005. After a first experience as chemical analyst engineer in the pharmaceutical industry, he joined a team at the CBS, a structural laboratory in Montpellier, to work on a Fragment-Based Drug Design strategy to develop protein-protein interaction inhibitors. In 2017, he joined the IBMM as CNRS engineer specialized in molecular interactions studies.

Sébastien is currently working at the interface between chemistry and biology with skills in molecular modelling and protein biochemistry. Then using several biophysics technics, he characterizes protein-protein and protein-ligand interactions.

Contact:
sebastien.estaran@umontpellier.fr
0033411759528

5 major publications :

« SAR predictions of benzoylphenylurea chitin synthesis inhibitors active on larvae of Aedes aegypti. » Devillers J., Doucet-Panaye A., Doucet J.-P., Lattes A., Matondo H., Lagneau C., Estaran S., Clémente M.-M., and Yébakima A.,2017. J. Devillers, ed., CRC Press, Boca Raton, FL, USA.

« Predicting the toxicity of piperidines against female adults of Aedes aegypti, in Computational Design of Chemicals for the Control of Mosquitoes and their Diseases. » Devillers J., Doucet-Panaye A., Doucet J.-P., Lagneau C., Estaran S., and Yébakima A., 2017. J. Devillers, ed., CRC Press, Boca Raton, FL, USA.

« Distinct amino acids in the C-linker domain of the Arabidopsis K+ channel KAT2 determine its subcellular localization and activity at the plasma membrane. » Nieves-Cordones M, Chavanieu A, Jeanguenin L, Alcon C, Szponarski W, Estaran S, Chérel I, Zimmermann S, Sentenac H, Gaillard I. Plant Physiol. 2014 Mar

« Fragment-based identification of a locus in the Sec7 domain of Arno for the design of protein-protein interaction inhibitors. » Rouhana J, Hoh F, Estaran S, Henriquet C, Boublik Y, Kerkour A, Trouillard R, Martinez J, Pugnière M, Padilla A, Chavanieu A. J Med Chem. 2013 Nov

« Kinetics of interaction between ADP-ribosylation factor-1 (Arf1) and the Sec7 domain of Arno guanine nucleotide exchange factor, modulation by allosteric factors, and the uncompetitive inhibitor brefeldin A. »

Rouhana J, Padilla A, Estaran S, Bakari S, Delbecq S, Boublik Y, Chopineau J, Pugnière M, Chavanieu A. » J Biol Chem. 2013 Feb

Site-specific grafting on titanium surfaces with hybrid temporin antibacterial peptides

J. Mater. Chem. B, 2018,6, 1782-1790. doi 10.1039/C8TB00051D

Abstract

Relying on a membrane-disturbing mechanism of action and not on any intracellular target, antimicrobial peptides (AMP) are attractive compounds to be grafted on the surface of implantable materials such as silicone catheters or titanium surgical implants. AMP sequences often display numerous reactive functions (e.g. amine, carboxylic acid) on their side chains and straightforward conjugation chemistries could lead to uncontrolled covalent grafting, random orientation, and non-homogenous density. To achieve an easy and site specific covalent attachment of unprotected peptides on titanium surfaces, we designed hybrid silylated biomolecules based on the temporin-SHa amphipathic helical antimicrobial sequence. With the grafting reaction being chemoselective, we designed five analogues displaying the silane anchoring function at the N-ter, C-ter or at different positions inside the sequence to get an accurate control of the orientation. Grafting density calculations were performed by XPS and the influence of the orientation of the peptide on the surface was clearly demonstrated by the measure of antimicrobial activity. Temporin amphipathic helices are described to permeabilize the bacterial membrane by interacting in a parallel orientation with it. Our results move in the direction of this mechanism as the selective grafting of hybrid temporin 2 through a lysine placed at the center of the peptide sequence, resulted in better biofilm growth inhibition of E. coli and S. epidermis than substrates in which temporins were grafted via their C- or N-terminus.

Inhibitors of kallikrein-related peptidases: An overview.

Med Res Rev. 2018 Mar;38(2):655-683. doi: 10.1002/med.21451.

Masurier N, Arama DP, El Amri C, Lisowski V.

Abstract

Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.

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.

Abstract

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.

GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation

Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4501-4506. doi: 10.1073/pnas.1712725115. Epub 2018 Apr 9

Damian M, Pons V, Renault P, M’Kadmi C, Delort B, Hartmann L, Kaya AI, Louet M, Gagne D, Ben Haj Salah K, Denoyelle S, Ferry G, Boutin JA, Wagner R, Fehrentz JA, Martinez J, Marie J, Floquet N, Galès C, Mary S, Hamm HE, Banères JL.

Abstract

IThe growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine-mediated Gi protein activation by modulating the conformation of its α-subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Gαi that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions.

Cecile Echalier, presents her PhD work in SCF video

Cecile worked in the ibmm peptide team during her PhD (2013-2016), in collaboration with Prof. Ahmad Mehdi (ICGM). She worked on the development of hybrid hydrogels for 3D printing and tissue engineering.  Now postdoctoral researcher in Heidelberg, she speaks about her PhD in a video realized by Société Chimique de France (SCF). Cecile was distinguished as ‘woman in science’ 2016 by Unesco&L’Oréal  for her research work in chemistry.

 

ORALCANCERPRINT

ORALCANCERPRINT
Biofabrication of an oral squamous cell carcinoma model by 3D bioprinting

Funding : Emergence, Cancéropôle Grand Sud-Ouest

June 2018 – June 2019

 

Nowadays, treatments of oral squamous cell carcinoma is principally based on excision surgery and can be associated with radiotherapy and chemotherapy. It is really important to have a better understanding of the neoplastic oral mucous membrane to develop less aggressive treatment. This project is a multidisciplinary project aiming at designing an oral squamous cell carcinoma model by 3D bioprinting, to help the development of cancer treatments.

The aim of the project is to develop an in vitro 3D organotipic model of oral mucous membrane with the help of 3D-bioprinting of cellularized layers. The use of two different 3D bioprinting technologies will allow to reproduce the architecture of cancer tissues at a macroscopic and a microscopic scale. Layers of hybrid collagenous peptide based hydrogel encapsulating gingival fibroblasts will be 3D printed by extrusion with layers of endothelial cells in the same hydrogel but 3D printed by a laser-assisted technology, to create a vascularized tissue. Finally, a layer of cancerous keratinocytes embedded into the hydrogel, printed by laser, will cover the model. The complexity of the model will give a better understanding of cellular communication in oral cancer and will be a platform for drug screening.

 

This project is developed in collaboration with BioTis Team ( Dr. Adrien Naveau and Dr. Raphael Devillar), Inserm 1026 : Tissular Bio-engineering team, Bordeaux.

THE TEAM

Gilles Subra
raphael devillard
RAPHAEL DEVILLAR (BioTis)
adrien naveau
ADRIEN NAVEAU (BioTis)
Ahmad Mehdi
AHMAD MEHDI
Laurine Valot
LAURINE VALOT