Eric Biron

Conformational and orientation studies of artificial ion channels incorporated into lipid bilayers

The conformational and orientation studies in lipid bilayers of 21 amino acid peptides bearing six crown ethers are reported. The compounds were designed to form artificial ion channels by stacking the crown rings, and were shown to be functional in bilayer membranes. We used Fourier transform infrared spectroscopy and CD spectropolarimetry to study the conformation of the peptides in solution and in lipid bilayers. These studies revealed that hexacrown peptides retain their alpha-helical conformation when incorporated in a lipid bilayer environment. Attenuated total reflectance spectroscopy was used to investigate the orientation of the peptides in a lipid bilayer. Results demonstrated that the peptides are not oriented at a fixed angle in membrane, but rather are in incorporation equilibrium between an active state parallel to the lipid chain and an inactive state adsorbed at the surface of the bilayer. From these results, we propose a model for the channel activity and the gating mechanism of these hexacrown peptides in bilayer membranes.

Thermoregulated Optical Properties of Peptidic Pseudorotaxanes

Natural peptide spine and artificial crown ether are blended together to form a hybrid structure. A dicationic benzylammonium guest threads through the crown ether pendants and the resulting noncovalent, self-assembled pseudorotaxane complex, shown schematically in the picture, is both stable and has optical properties dependant on temperature.

Membrane disruption ability of facially amphiphilic helical peptides

A helical 14-residue peptide containing four polar, but uncharged, benzo-21-crown-7 side-chains aligned along one face induces significantly more vesicle leakage than analogous 21-mer or 7-mer peptides.

Machine learning assisted design of highly active peptides for drug discovery

The discovery of peptides possessing high biological activity is very challenging due to the enormous diversity for which only a minority have the desired properties. To lower cost and reduce the time to obtain promising peptides, machine learning approaches can greatly assist in the process and even partly replace expensive laboratory experiments by learning a predictor with existing data or with a smaller amount of data generation. Unfortunately, once the model is learned, selecting peptides having the greatest predicted bioactivity often requires a prohibitive amount of computational time. For this combinatorial problem, heuristics and stochastic optimization methods are not guaranteed to find adequate solutions. We focused on recent advances in kernel methods and machine learning to learn a predictive model with proven success. For this type of model, we propose an efficient algorithm based on graph theory, that is guaranteed to find the peptides for which the model predicts maximal bioactivity. We also present a second algorithm capable of sorting the peptides of maximal bioactivity. Extensive analyses demonstrate how these algorithms can be part of an iterative combinatorial chemistry procedure to speed up the discovery and the validation of peptide leads. Moreover, the proposed approach does not require the use of known ligands for the target protein since it can leverage recent multi-target machine learning predictors where ligands for similar targets can serve as initial training data. Finally, we validated the proposed approach in vitro with the discovery of new cationic antimicrobial peptides. Source code freely available at http://graal.ift.ulaval.ca/peptide-design/.

Practical ring-opening strategy for the sequence determination of cyclic peptides from one-bead-one-compound libraries.

The use of cyclic peptides in one-bead-one-compound libraries is limited by difficulties in sequencing hit compounds. Lacking a free N-terminal amine, such peptides cannot be sequenced by the Edman degradation approach, and complex fragmentation patterns are obtained by tandem mass spectrometry. To overcome this problem, we designed an alternative approach introducing a methionine residue within the macrocycle and as a linker to allow simultaneous ring-opening and release from the resin upon treatment with cyanogen bromide. The methionine linker was inverted relative to the peptide chain to allow the synthesis of cyclic peptides anchored by a lysine side chain and to avoid the presence of two C-terminal homoserine lactones on the released linear peptides. After MALDI-TOF MS/MS analysis, the peptides released from a single bead were sequenced manually and with a de novo sequencing software. The strategy described herein is compatible with commonly used amino acids and allows sequencing of cyclic peptides in one-bead-one-compound libraries, thus reducing the need for encoding.

Synthesis of cationic porphyrin modified amino acids

Derivatives of amino acids bearing a porphyrin moiety on a side chain were synthesized by coupling a porphyrin to a glutamic acid side chain; the utility of these compounds was demonstrated by their use in solid-phase synthesis of a peptide bearing a cationic porphyrin and by studying its DNA-binding properties.

Chiral recognition of carboxylic acids by bis-crown ether peptides

Abstract The conformation of crown ether modified peptides induced by the complexation of Z-Phe-OH and Z-Ala-OH cesium salts allows the formation of distinct chiral complexes. Both enantiomers of these protected amino acids can be distinguished by 1H NMR and enantioselective transport could be effected. The chiral recognition ability is dependent on the amino acid sequence of the peptidic frameworks and on the position of the crown ether side chains.

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.

A Convenient Approach to Prepare Topologically Segregated Bilayer Beads for One-Bead Two-Compound Combinatorial Peptide Libraries

One-bead one-compound (OBOC) combinatorial peptide libraries have been used to identify ligands and modulators for a wide variety of biological targets. While being very efficient with linear peptides, OBOC libraries with N-terminally blocked peptides or with unsequenceable building blocks require encoding. To fully exploit OBOC combinatorial methods with cyclic peptides and peptidomimetics, topologically segregated bilayer beads have been developed. This strategy offers the opportunity to synthesize two compounds per bead, i.e. with one compound exposed on the bead surface for screening, and the other one found within the inner layer as a tag for sequencing and compound identification. Bead segregation often involves the use of unstable derivatives or requires a series of protection–deprotection steps. In order to expedite and optimize bead segregation, the performance of various reagents has been studied. The results obtained herein show that bead segregation can be efficiently performed with commercially available reagents. Finally, in order to control outer/inner layer ratios in segregated beads, the effects of different parameters have been evaluated. We report a straightforward and efficient procedure to prepare topologically segregated bilayer beads in a wide range of controllable, predictable, and reproducible outer versus inner ratios.

One-Pot Photochemical Ring-Opening/Cleavage Approach for the Synthesis and Decoding of Cyclic Peptide Libraries.

A novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one bead, one compound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of five to nine residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.