Author: Lubomir Vezenkov

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

Abstract

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.

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.

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.