Molecular docking studies towards development of novel Gly-Phe analogs for potential inhibition of Cathepsin C (dipeptidyl peptidase I)

Cathepsin C is a cysteine protease required for activation of various pro-inflammatory serine proteases and, essentially, is of interest as a therapeutic target. Cathepsin C coordinate system was employed as a model to study the interaction of some already available inhibitors of Cathepsin C. Compounds containing Gly-Phe fragment with functional groups at its ends were designed by knowledge based approach. Using AutoDock and Discovery Studio Client 3.1 software packages, binding energy of different conformations and ten scoring functions (LigScore1, LigScore2, PLP1, PLP2, JAIN, PMF, PMF04, LUDI_1, LUDI_2 and LUDI_3) were calculated for newly designed compounds. These docking studies revealed favorable energy scores which also helps to understand interaction of ligands with enzyme

Peptide stapling by late-stage Suzuki-Miyaura cross-coupling

The development of peptide stapling techniques to stabilise alpha-helical secondary structure motifs of peptides led to the design of modulators of protein-protein interactions, which had been considered undruggable for a long time. We disclose a novel approach towards peptide stapling utilising macrocyclisation by late-stage Suzuki-Miyaura cross-coupling of bromotryptophan-containing peptides of the catenin-binding domain of axin. Optimisation of the linker length in order to find a compromise between both sufficient linker rigidity and flexibility resulted in a peptide with an increased alpha-helicity and enhanced binding affinity to its native binding partner beta-catenin. An increased proteolytic stability against proteinase K has been demonstrated

1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties

Schröder DC, Kracker O, Fröhr T, et al. 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties. Frontiers in Chemistry. 2019;7: 155.Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1H-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1H-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and α-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Ψ[4Tz]Phe-LeuΨ[4Tz]Phe-LeuΨ[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(AlaΨ[4Tz]Ala)6-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)6-OAll and Boc-Ala-(GlyΨ[4Tz]Ala)6-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted “S”-shape, while the Gly variant exhibits no clear secondary structure

Protein surface mimetics: understanding how ruthenium tris(bipyridines) interact with proteins.

Protein surface mimetics achieve high affinity binding by exploiting a scaffold to project binding groups over a large area of solvent exposed protein surface to make multiple co-operative non-covalent interactions. Such recognition is a pre-requisite for competitive/ orthosteric inhibition of protein-protein interactions (PPIs). This paper describes biophysical and structural studies on ruthenium(II) tris(bipyridine) surface mimetics that recognize cytochrome (cyt) c and inhibit the cyt c/ cyt c peroxidase (CCP) PPI. Binding is electrostatically driven, with enhanced affinity achieved through enthalpic contributions thought to arise from the ability of the surface mimetics to make a greater number of non-covalent interactions with surface exposed basic residues on cyt c in comparison to CCP. High field natural abundance 1H-15N HSQC NMR experiments are consistent with surface mimetics binding to cyt c in similar manner to CCP. This provides a framework for understanding recognition of proteins by supramolecular receptors and informing the design of ligands superior to the protein partners upon which they are inspired

Solution Observation of Dimerization and Helix Handedness Induction in a Human Carbonic Anhydrase-Helical Aromatic Amide Foldamer Complex

The design of synthetic foldamers to selectively bind proteins is currently hindered by the limited availability of molecular data to establish key features of recognition. Previous work has described dimerization of human carbonic anhydraseII (HCA) through self-association of a quinoline oligoamide helical foldamer attached to a tightly binding HCA ligand. A crystal structure of the complex provided atomic details to explain the observed induction of single foldamer helix handedness and revealed an unexpected foldamer-mediated dimerization. Here, we investigated the detailed behavior of the HCA-foldamer complex in solution by using NMR spectroscopy. We found that the ability to dimerize is buffer-dependent and uses partially distinct intermolecular contacts. The use of a foldamer variant incapable of self-association confirmed the ability to induce helix handedness separately from dimer formation and provided insight into the dynamics of enantiomeric selection

Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP)

Urbanczyk M, Jewginski M, Krzciuk-Gula J, Gora J, Latajka R, Sewald N. Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP). Beilstein Journal of Organic Chemistry . 2019;15:1581-1591.Antifreeze glycoproteins are a class of biological agents which enable living at temperatures below the freezing point of the body fluids. Antifreeze glycopeptides usually consist of repeating tripeptide unit (-Ala-Ala-Thr*-), glycosylated at the threonine side chain. However, on the microscopic level, the mechanism of action of these compounds remains unclear. As previous research has shown, antifreeze activity of antifreeze glycopeptides strongly relies on the overall conformation of the molecule as well an on the stereochemistry of amino acid residues. The desired monoglycosylated analogues with acetylated amino termini and the carboxy termini in form of N-methylamide have been synthesized. Conformational nuclear magnetic resonance (NMR) studies of the designed analogues have shown a strong influence of the stereochemistry of amino acid residues on the peptide chain stability, which could be connected to the antifreeze activity of these compounds. A better understanding of the mechanism of action of antifreeze glycopeptides would allow applying these materials, e.g., in food industry and biomedicine

Self-Assembled Protein–Aromatic Foldamer Complexes with 2:3 and 2:2:1 Stoichiometries

The promotion of protein dimerization using the aggregation properties of a protein ligand was explored and shown to produce complexes with unusual stoichiometries. Helical foldamer <b>2</b> was synthesized and bound to human carbonic anhydrase (HCA) using a nanomolar active site ligand. Crystal structures show that the hydrophobicity of <b>2</b> and interactions of its side chains lead to the formation of an HCA₂-<b>2</b>₃ complex in which three helices of <b>2</b> are stacked, two of them being linked to an HCA molecule. The middle foldamer in the stack can be replaced by alternate sequences <b>3</b> or <b>5</b>. Solution studies by CD and NMR confirm left-handedness of the helical foldamers as well as HCA dimerization

Self-Assembled Protein–Aromatic Foldamer Complexes with 2:3 and 2:2:1 Stoichiometries

The promotion of protein dimerization using the aggregation properties of a protein ligand was explored and shown to produce complexes with unusual stoichiometries. Helical foldamer <b>2</b> was synthesized and bound to human carbonic anhydrase (HCA) using a nanomolar active site ligand. Crystal structures show that the hydrophobicity of <b>2</b> and interactions of its side chains lead to the formation of an HCA₂-<b>2</b>₃ complex in which three helices of <b>2</b> are stacked, two of them being linked to an HCA molecule. The middle foldamer in the stack can be replaced by alternate sequences <b>3</b> or <b>5</b>. Solution studies by CD and NMR confirm left-handedness of the helical foldamers as well as HCA dimerization

VCD studies on cyclic peptides assembled from L-alpha-amino acids and a trans-2-aminocyclopentane- or trans-2-aminocyclohexane carboxylic acid

Vass E, Strijowski U, Wollschlaeger K, et al. VCD studies on cyclic peptides assembled from L-alpha-amino acids and a trans-2-aminocyclopentane- or trans-2-aminocyclohexane carboxylic acid. Journal of Peptide Science. 2010;16(11):613-620.The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans-2-aminocyclohexane carboxylic acid (Achc) or trans-2-aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three-dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6-31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR-based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides. Copyright 2010 European Peptide Society and John Wiley & Sons, Ltd

1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties

Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-dlsubstltuted 1H-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1H-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and a-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Psi[4Tz]Phe-Leu Psi[4Tz]Phe-Leu Psi[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(Ala Psi[4Tz]Ala)(6)-OAll as well as Boc-Ala-(D-Ala Psi[4Tz]Ala)(6)-OAll and Boc-Ala-(Gly Psi[4Tz]Ala)(6)-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted "S"-shape, while the Gly variant exhibits no clear secondary structure