Rapid Formation of Intramolecular Disulfide Bridges using Light: An Efficient Method to Control the Conformation and Function of Bioactive Peptides.

Disulfide bonds are widely found in natural peptides and play a pivotal role in stabilizing their secondary structures, which are highly associated with their biological functions. Herein, we introduce a light-mediated strategy to effectively control the formation of disulfides. Our strategy is based on 2-nitroveratryl (Nv), a widely used photolabile motif, which serves both as a photocaging group and an oxidant (after photolysis).

Diversity in the Synthesis of Functionalized Cyclohexene Oxide Derivatives by a Cycloaddition-Fragmentation Sequence from Benzene Oxide.

A cycloaddition-fragmentation sequence from benzene oxide and a nitroso- or azo-dienophile was investigated as a tool for access to highly substituted cyclohexene oxide derivatives. Alkyl lithium-promoted fragmentation of the cycloadducts led to the cyclic derivatives after 1,4- or 1,2-addition of a second equivalent of the lithium reagent. New fragmentation processes were observed when using non-nucleophilic bases of highly hindered alkyl lithium reagents.

Using the Noncanonical Metallo-Amino Acid [Cu(II)(2,2'-Bipyridin-5-yl)]-alanine to Study the Structures of Proteins.

Genetic code expansion allows modification of the physical and chemical properties of proteins by the site-directed insertion of noncanonical amino acids. Here we exploit this technology for measuring nanometer-scale distances in proteins. (2,2'-Bipyridin-5-yl)alanine was incorporated into the green fluorescent protein (GFP) and used as an anchoring point for Cu(II) to create a spin-label.

Customized Reversible Stapling for Selective Delivery of Bioactive Peptides.

We have developed a new concept for reversible peptide stapling that involves macrocyclization between two amino groups and decyclization promoted via dual 1,4-elimination. Depending on the trigger moiety, this strategy could be employed to selectively deliver peptides to either intracellular or extracellular targets. As a proof of concept, a peptide inhibitor targeting a lysine-specific demethylase 1 (LSD1) was temporarily cyclized to enhance its stability and ability to cross the cell membrane.

Polymyxin B-inspired non-hemolytic tyrocidine A analogues with significantly enhanced activity against gram-negative bacteria: How cationicity impacts cell specificity and antibacterial mechanism.

Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic lipopeptide polymyxin B (PMB), the so called 'last-resort' antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A.

Gramicidin-S-Inspired Cyclopeptidomimetics as Potent Membrane-Active Bactericidal Agents with Therapeutic Potential.

Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using β,γ-diamino acids (β,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects.

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids.

Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs).

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide.

Gramicidin S (GS), one of the oldest commercially used peptide antibiotics, is known for its robust antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Although it was discovered well over 70 years ago, its clinical potential was limited to topical applications because of its high hemolytic activity. To overcome this side effect, significant efforts have been invested in the chase for GS analogues with high therapeutic index (e.

Unexpected dimerization of a tripeptide comprising a β,γ-diamino acid.

We have previously reported the synthesis of enantiopure β,γ-diamino acids and relevant short α/γ-peptide containing such building blocks. Complete nuclear magnetic resonance (NMR) studies, together with molecular modeling, highlighted the ability of a β,γ-diamino acid to induce various intramolecular turns. In this paper, we describe for the first time the formation of a dimeric structure constituted by α/γ/α-tripeptide and stabilized by intermolecular interactions.

Oxidative coupling of enolates using memory of chirality: an original enantioselective synthesis of quaternary α-amino acid derivatives.

We describe here the first enantioselective oxidative heterocoupling of enolates. Our strategy relies on the memory of chirality concept and allows the stereocontrolled formation of quaternary centres on α-amino acid derivatives with an enantiomeric excess of up to 94%.

Base-Mediated Fragmentation of Bicyclic Dihydro-3,6-oxazines: Transformation of Nitroso Diels-Alder Cycloadducts.

Nitroso Diels-Alder cycloadditions of benzene oxide with various acyl-nitroso derivatives are described. Treatment of these cycloadducts with methyllithium results in a fast fragmentation reaction, leading to highly functionalized cyclic amino alcohols. The mechanism of the reaction and the role of the epoxide in the fragmentation process are investigated.

β,γ-diamino acids as building blocks for new analogues of Gramicidin S: Synthesis and biological activity.

We describe here the synthesis and biological activity study of a pair of diastereomeric analogues of Gramicidin S using β,γ-diamino acids as β-turn mimic. The synthesis of the orthogonally protected β,γ-diamino acids was achieved in 6 steps starting from d-alanine. The analogues were then synthesized in solution phase and on solid phase.

Interfering peptides targeting protein-protein interactions: the next generation of drugs?

Protein-protein interactions (PPIs) are well recognized as promising therapeutic targets. Consequently, interfering peptides (IPs) - natural or synthetic peptides capable of interfering with PPIs - are receiving increasing attention. Given their physicochemical characteristics, IPs seem better suited than small molecules to interfere with the large surfaces implicated in PPIs.

Frozen Chirality of Tertiary Aromatic Amides: Access to Enantioenriched Tertiary α-Amino Acid or Amino Alcohol without Chiral Reagent.

One of the fundamental and intriguing aspects of life is the homochirality of the essential molecules. In this field, the absolute asymmetric synthesis of α-amino acids is a major challenge. Herein, we report access, by chemical means, to tertiary α-amino acid derivatives in up to 96 % ee without using any chiral reagent.

Efficient synthesis of both diastereomers of β,γ-diamino acids from phenylalanine and tryptophan.

We synthesized in a few steps both diastereomers of orthogonally protected β,γ-diamino acids starting from L-phenylalanine or L-tryptophan. These final compounds are interesting building blocks for peptide synthesis and foldamer chemistry. The key step is a Blaise reaction performed under ultrasound conditions.

Β,γ-diamino acid: an original building block for hybrid α/γ-peptide synthesis with extra hydrogen bond donating group.

Using a β,γ-diamino acid, several small hybrid α/γ peptides have been synthesized and their conformations investigated through extensive NMR studies and molecular dynamics. A tripeptide and a tetrapeptide have thus shown several hydrogen bonds in solution, including a 13-membered ring involving the β-nitrogen.

Substrate control in enantioselective and diastereoselective aldol reaction by memory of chirality: a rapid access to enantiopure β-hydroxy quaternary α-amino acids.

An asymmetric aldol reaction by memory of chirality is reported with a substrate control of stereoselectivity by aldehyde and rationalized. Starting from l-alanine, several diastereopure and enantioenriched β-hydroxy quaternary α-amino acids have been obtained in three steps. The initial chirality of l-alanine is memorized through the dynamic axial chirality of tertiary aromatic amide.

Original β,γ-diamino acid as an inducer of a γ-turn mimic in short peptides.

Original αγα tripeptides containing one β,γ-diamino acid have been synthesized and their conformation determined by extensive NMR and molecular dynamic studies. These studies revealed the presence of a C(9) hydrogen bonded turn around the β,γ-diamino acid which was stabilized by bulky side chains of the preceding residue. This turn can be considered as a mimic of the well-known γ-turn.

Memory of chirality of tertiary aromatic amide: application to the asymmetric synthesis of (S)-α-methylDOPA.

We describe an original asymmetric synthesis of (S)-α-methylDOPA proceeding by the concept of memory of chirality, the only source of chirality being the starting D-alanine. The initial chirality of the amino acid is temporarily transferred to a dynamic axial chirality of a tertiary aromatic amide. The (S)-α-methylDOPA hydrochloride is obtained after four steps with 98% ee.

Absolute asymmetric synthesis of tertiary α-amino acids.

Frozen: the spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the deprotonation/alkylation. α-Amino acid derivatives are synthesized in up to 96 % ee.

Constrained α/γ-peptides: a new stable extended structure in solution without any hydrogen bond and characterized by a four-fold symmetry.

Small α/γ-peptides alternating α-aminoisobutyric acid and cyclic γ-amino acid residues are described. NMR studies together with restrained simulated annealing revealed that an extended backbone conformation largely dominates in solution for as short as 4-residues long oligomers. This new fold type is devoid of any hydrogen bond and characterized by a four-fold symmetry.

Foldamers containing γ-amino acid residues or their analogues: structural features and applications.

Over the past 20 years, the field of foldamers has rapidly increased. Many β-peptides have already been described and shown interesting properties. γ-Peptides have more recently emerged but seem to be very interesting as well.

Access to β,γ-diamino acids. Application to the synthesis of 3-deoxyaminostatine.

The synthesis of orthogonally protected diastereo- and enantiopure β,γ-diamino acids starting from natural α-amino acids is described, as well as its application to the synthesis of fully protected 3-deoxyaminostatine.