0000000000082381
AUTHOR
Rafał Latajka
Pentapeptides containing two dehydrophenylalanine residues - synthesis, structural studies and evaluation of their activity towards cathepsin C
Synthesis, structural and biological studies of pentapeptides containing two Delta Phe residues (Z and E isomers) in position 2 and 4 in peptide chain were performed. All the investigated peptides adopted bent conformation and majority of them could exist as two different. conformers in solution. Only pentapeptides. containing free N-termini appeared to act as weak inhibitors of cathepsin C with the slow-binding, competitive mechanism of inhibition. free acids being bound slightly better than their methyl esters. Results of Molecular modeling suggested significant difference between peptides, depending of the type of amino acid residue in position 5 in peptide chain. Dehydropeptides contain…
Addition of thiols to the double bond of dipeptide C-terminal dehydroalanine as a source of new inhibitors of cathepsin C.
Addition of thiols to double bond of glycyl-dehydroalanine and phenyl-dehydroalanine esters provided micromolar inhibitors of cathepsin C. The structure-activity studies indicated that dipeptides containing N-terminal phenylalanine exhibit higher affinity towards the enzyme. A series of C-terminal S-substituted cysteines are responsible for varying interaction with S1 binding pocket of cathepsin C. Depending on diastereomer these compounds most likely act as slowly reacting substrates or competitive inhibitors. This was proved by TLC analysis of the medium in which interaction of methyl (S)-phenylalanyl-(R,S)-(S-adamantyl)cysteinate (7i) with the enzyme was studied. Molecular modeling enabl…
Conformational investigations of bis(α-aminoalkyl)phosphinic acids and studies of the stability of their complexes with Cu(II)
Abstract Conformational investigations of a group of bis(α-aminoalkyl)phosphinic acids were performed by use of NMR spectroscopy and theoretical calculations. In the case of one of the studied compounds, substituted with aminobenzyl and amino(p-chlorobenzyl) moieties, a pH-dependent equilibrium between conformers, stabilized by intermolecular hydrogen bonds was observed. Potentiometric studies proved that these molecules formed stable complexes with copper(II) ions, where stoichiometry was 1:1 and 1:2 depending on pH of their aqueous solution.
Influence of solvents on conformation of dehydropeptides
Abstract Structural investigations of dehydropeptides containing (Z)-dehydrophenylalanine in solvents characterized by different polarity are discussed. The conformational analysis are based on spectroscopic methods (NMR, CD), molecular modeling techniques and in case of the tripeptide, ab initio methods. The results of temperature experiment indicate, that the only conformation of the investigated hexapeptide 3 is stabilized by intramolecular hydrogen bonds. Depending on the length of the peptide chain, the polarity of solvent influences on arrangement of the side chain of the amino acids or of the main chain of the peptide.
Toward engineering efficient peptidomimetics. Screening conformational landscape of two modified dehydroaminoacids
Effective peptidomimetics should posses structural rigidity and appropriate interaction pattern leading to potential spatial and electronic matching to the target receptor site. Rational design of such small bioactive molecules could push chemical synthesis and molecular modeling toward faster progress in medicinal chemistry. Conformational properties of N-t-butoxycarbonyl-glycine-(E/Z)-dehydrophenylalanine N′,N′-dimethylamides (Boc-Gly-(E/Z)-ΔPhe-NMe2) in chloroform were studied by NMR and IR spectroscopy. The experimental findings were supported by extensive calculations at DFT(B3LYP, M06-2X) and MP2 levels of theory and the β-turn tendency for both isomers of the studied dipeptide were d…
Conformation of dehydropentapeptides containing four achiral amino acid residues - controlling the role of L-valine.
Structural studies of pentapeptides containing an achiral block, built from two dehydroamino acid residues (ΔZPhe and ΔAla) and two glycines, as well as one chiral L-Val residue were performed using NMR spectroscopy. The key role of the L-Val residue in the generation of the secondary structure of peptides is discussed. The obtained results suggest that the strongest influence on the conformation of peptides arises from a valine residue inserted at the C-terminal position. The most ordered conformation was found for peptide Boc-Gly-ΔAla-Gly-ΔZPhe-Val-OMe (3), which adopts a right-handed helical conformation.
Unnatural amino acids increase activity and specificity of synthetic substrates for human and malarial cathepsin C
Mammalian cathepsin C is primarily responsible for the removal of N-terminal dipeptides and activation of several serine proteases in inflammatory or immune cells, while its malarial parasite ortholog dipeptidyl aminopeptidase 1 plays a crucial role in catabolizing the hemoglobin of its host erythrocyte. In this report, we describe the systematic substrate specificity analysis of three cathepsin C orthologs from Homo sapiens (human), Bos taurus (bovine) and Plasmodium falciparum (malaria parasite). Here, we present a new approach with a tailored fluorogenic substrate library designed and synthesized to probe the S1 and S2 pocket preferences of these enzymes with both natural and a broad ran…
Stereochemistry of terpene derivatives. Part 4:☆ Fragrant terpenoid derivatives with an unsaturated gem-dimethylbicyclo[3.1.0]hexane system
Abstract Starting from (+)-3-carene 1 several chiral fragrant compounds with the bicyclo[3.1.0]hexane system 4–6 and 10–20 were synthesized. These compounds are structural analogues of naturally occurring fragrant compounds, such as ionones and damascones, and possess either an endo- or an exo-cyclic double bond in the bicyclo[3.1.0]hexane moiety. The absolute configuration of selected products was confirmed by X-ray crystallography and circular dichroism analysis.
Peptide p-nitrophenylanilides containing (E)-dehydrophenylalanine—synthesis, structural studies and evaluation of their activity towards cathepsin C
Tetrapeptide p-nitroanilides containing (E)-dehydrophenylalanine were synthesized and evaluated as inhibitors and substrates of cathepsin C. Peptides containing a free, unblocked amino group appeared to be quite good substrates of the enzyme, whereas fully protected peptides acted as very weak inhibitors. Structural studies by means of NMR and CD, alongside with molecular modelling, have proved that these peptides are hydrolysed in one step by direct removal of p-nitroaniline from the tetrapeptide.
Effect of the ΔPhe residue configuration on a didehydropeptides conformation: A combined CD and NMR study.
Conformations of two pairs of dehydropeptides with the opposite configuration of the ΔPhe residue, Boc-Gly-Δ(Z)Phe-Gly-Phe-OMe (Z-OMe), Boc-Gly-Δ(E)Phe-Gly-Phe-OMe (E-OMe), Boc-Gly-Δ(Z)Phe-Gly-Phe-p-NA (Z-p-NA), and Boc-Gly-Δ(E)Phe-Gly-Phe-p-NA (E-p-NA) were compared on the basis of CD and NMR studies in MeOH, trifluoroethanol (TFE), MeCN, chloroform, and dimethylsulfoxide (DMSO). The CD results were used as the additional input data for the NMR-based determination of the detailed solution conformations of the peptides. It was found that E-OMe is unordered and Z-OMe, Z-p-NA, and E-p-NA adopt the β-turn conformation. There are two overlapping β-turns in each of those peptides: type II and ty…
Phosphinotripeptidic Inhibitors of Leucylaminopeptidases
Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is …
“Twin” phosphorous atoms of tetraethyl 2-methyl-piperyd-1-ylmethylenebisphosphonates
Recently, bisaminophosphonates found applications as therapeutic agents for curing bone disorders. When trying to relate the structures of substituted piperid-1-ylmethylenebisphosphonic with their biological properties, non-typical findings that in 31P NMR spectra of 2-methyl-piperid-1-ylmethylenebisphosphonic and 2-ethyl-piperid-1-ylmethylenebisphosphonic acids, two separate singlets from each of the phosphonic groups were observed, while their analogues bearing substituent in position 3 exhibit only one signal. Their presence was explained by freezing of the molecular motions by strong hydrogen bonding between NH and P = O atoms. In this work, synthesis as well as spectroscopic and theore…
Synthesis of Hybrid Tripeptide Peptidomimetics Containing Dehydroamino Acid and Aminophosphonic Acid in the Chain and Evaluation of Their Activity toward Cathepsin C
Synthesis of a new group of hybrid phosphonodehydropeptides composed of glycyl-(Z)-dehydrophenylalanine and structurally variable aminophosphonates alongside with investigations of their activity towards cathepsin C are presented. Obtained results suggest that the introduction of (Z)- dehydrophenylalanine residue into the short phosphonopeptide chain does induce the ordered conformation. Investigated peptides appeared to act as weak or moderate inhibitors of cathepsin C.
Conformational studies of hexapeptides containing two dehydroamino acid residues in positions 3 and 5 in peptide chain
Abstract Synthesis and structural studies of hexapeptides containing two dehydroamino acid residues in positions 3 and 5 in a peptide chain were performed. All the investigated peptides adopted bent conformations, stabilized by intramolecular hydrogen bonding, and could exist as two different conformers in solution. Only in the case of the peptide containing ΔAla residues, expected 3 10 -helical conformation was found.
Synthesis of Tetrapeptide p‐nitrophenylanilides containing dehydroalanine and dehydrophenylalanine and their influence on cathepsin C activity
Three dehydrotetrapeptides of rationally varying structure were prepared and tested as affectors of cathepsin C. These compounds appeared to be substrates of the enzyme, being equipotent with their classical counterparts. Thus, replacement of amino acid in a short peptide by corresponding dehydroamino acid does not prevent cathepsin C in recognizing dehydropeptide as its substrate. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.
Conformational studies of hexapeptides containing two dehydroamino acid residues in positions 2 and 5 in peptide chain
Conformational preferences of a group of hexapeptides containing two dehydroamino acid residues in Positions 2 and 5 in peptide chain were investigated by means of spectroscopic methods (NMR and CD) and theoretical calculations. In the case of dimethylsulfoxide (DMSO) solution, only peptide with free N-termini adopted rigid 310-helical conformation, for the rest of examined peptides extended and “zig-zag” conformers were predominant. CD measurements showed that only in chloroform solution the conformational freedom of investigated peptides was restricted. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 691–699, 2008. This article was originally published online as an accepted preprint. The “…
Combined effect of the DeltaPhe or DeltaAla residue and the p-nitroanilide group on a didehydropeptides conformation.
Two series of dehydropeptides of the general formulae Boc-Gly-X-Phe-p-NA, Boc-Gly-Gly-X-Phe-p-NA, Gly-X-Gly-Phe-p-NA·TFA, and Boc-Gly-X-Gly-Phe-p-NA, with X = ΔZPhe and ΔAla, were studied with NMR in DMSO and CDCl3-DMSO, and with CD in MeOH, MeCN, and TFE. The NMR spectra measured in DMSO suggest that peptides with the ΔPhe residue next to Phe are folded whereas peptides with Gly between ΔPhe and Phe are less ordered. NMR spectra of ΔAla-containing peptides indicate that these peptides are flexible and their conformational equilibria are populated by many different conformations. The CD spectra show that conformational properties of the peptides studied are distinctly influenced by a mutual…