Author: Lubomir Vezenkov

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.

Abstract

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.

IBMM peptide promoting science to highschool teachers!

Team Peptide is involved with vulgarisation of science ! It was our pleasure and privilege to receive eight high school teachers from the south of France reagion! At the pictures Laurine Valot, Gilles Subra and Lubomir Vezenkov animating a workshop on 3d printing of peptide materials and solid phase peptide synthesis.

A new ultra high performance equipment for IBMM and our team!

IBMM has recently acquired this wonderful UPLC and mass-spectrometry toy! It is an Aquity Hclass UPLC (Pierre Sanchez to the left, the engeneer that operates it) produced by Waterstm that can sustain the amazing 15000 psi! While other HPLC would crumble under such pressure this fine equipment provides an amazing HPLC separation! Getting to 95% purity just got harder in our team!

Marcrilen approved by the The European Medicines Agency!

The European Medicines Agency (EMA) has granted marketing authorization for MacrilenTM (JMV 1843), an orally available ghrelin agonist developed in our team ! Macrilen is used for diagnosis of adult growth hormone deficiency (AGHD). The approval came following the Committee for Medicinal Products for Human Use (CHMP) positive opinion of MacrilenTM.

People who have AGHD can include those who were GH deficient as children and become adults with AGHD, or adults who become GH deficient. In adults, GH deficiency could develop when your pituitary gland or hypothalamus is damaged due to tumors, surgery, radiation, or traumatic brain injury. GH is important for adults to support healthy tissue and organs. GH is released in pulses, so measuring your blood for too little GH (also known as a deficiency) may be hard. MacrilenTM, orally administered, will stimulate GH secretion in the circulation, which level can then be evaluated by simple blood samples.

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.