Synthesis of aldehydic peptides inhibiting renin

Fehrentz, Jean‐Alain; Heitz, Annie; Castro, Bertrand

doi:10.1111/j.1399-3011.1985.tb03201.x

Cited by 35 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this case, a reduced bond is formed in situ on the solid phase and needs no additional treatment. For this synthesis, a protected arginine aldehyde was obtained by reduction of N α ‐Boc,N G Z‐Arg lactame with lithium alumohydride in tetrahydrofuran followed by 1 H‐NMR‐spectroscopy characterization . The products of the solid phase synthesis, [Arg 1 (Z)]‐PIK5 and [Arg 1 (Z)]‐PIK6, were released by TFA.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Design of peptidase-resistant peptide inhibitors of myosin light chain kinase

et al. 2016

View full text Add to dashboard Cite

Myosin light chain kinase (MLCK) is a key regulator of various forms of cell motility including smooth muscle contraction, cell migration, cytokinesis, receptor capping, secretion, etc. Inhibition of MLCK activity in endothelial and epithelial monolayers using cell-permeant peptide Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys (PIK, Peptide Inhibitor of Kinase) allows protecting the barrier capacity, suggesting a potential medical use of PIK. However, low stability of L-PIK in a biological milieu prompts for development of more stable L-PIK analogues for use as experimental tools in basic and drug-oriented biomedical research. Previously, we designed PIK1, H-(N Me)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH , that was 2.5-fold more resistant to peptidases in human plasma in vitro than L-PIK and equal to it as MLCK inhibitor. In order to further enhance proteolytic stability of PIK inhibitor, we designed the set of six site-protected peptides based on L-PIK and PIK1 degradation patterns in human plasma as revealed by H-NMR analysis. Implemented modifications increased half-live of the PIK-related peptides in plasma about 10-fold, and these compounds retained 25-100% of L-PIK inhibitory activity toward MLCK in vitro. Based on stability and functional activity ranking, PIK2, H-(N Me)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-D-Arg-Lys-NH , was identified as the most stable and effective L-PIK analogue. PIK2 was able to decrease myosin light chain phosphorylation in endothelial cells stimulated with thrombin, and this effect correlated with the inhibition by PIK2 of thrombin-induced endothelial hyperpermeability in vitro. Therefore, PIK2 could be used as novel alternative to other cell-permeant inhibitors of MLCK in cell culture-based and in vivo studies where MLCK catalytic activity inhibition is required. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

show abstract

Section: Resultsmentioning

confidence: 99%

“…in DMF containing 1% acetic acid . Boc‐Arg(Z)‐H aldehyde was obtained by reduction of the corresponding lactame with lithium alumohydride in tetrahydrofuran followed by characterization of the product by means of 1 H‐NMR‐spectroscopy . Kaiser (ninhydrin) test was employed to analyze the completeness of the reaction.…”

Section: Methodsmentioning

confidence: 99%

Design of peptidase-resistant peptide inhibitors of myosin light chain kinase

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Several modifications involving the Pro 3 residue were thus carried out in order to modify the structural constraints, including the introduction of the more polar 4-hydroxyproline (Hyp), the acyclic sarcosine (Sar), the six-membered pipecolic acid (Pip), the bicyclic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Tic), the thiazolidine-4-carboxylic acid (Thz), and the β-analogue aminobenzoic acid (Abz) (Table 2, compounds 53−58). Although most of the attempts resulted in a decreased affinity (53,54,56,58), addition of one more sulfur atom by the use of Thz (57) produced an 88% displacement of the Stagged reference peptide 22. This promising result led us to pursue optimization with the association of Pen residue in position 1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…50−53 Its incorporation into the peptide sequence required the synthesis of the Weinreb amide derivative obtained by coupling the Weinreb amine (3 equiv) with the appropriate Fmoc-amino acid in standard coupling conditions, with DIEA (4 equiv) as the base and BOP (3 equiv) as the activating agent. 54 The subsequent reduction was performed using lithium aluminum hydride (6 equiv) in THF without further purification of the Weinreb amine. The aldehyde was an unstable intermediate, 55 which was condensed immediately to the growing peptide chain by reductive amination, on solid support under nitrogen with sodium cyanoborohydride (8 equiv) as a reductive agent in anhydrous DMF containing 1% acetic acid.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Chemical Optimization of New Ligands of the Low-Density Lipoprotein Receptor as Potential Vectors for Central Nervous System Targeting

Malcor

Payrot

David³

et al. 2012

J. Med. Chem.

View full text Add to dashboard Cite

Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

show abstract

“…The configuration of the C-terminal residue and its possible epimerization was studied in both strategies. As described earlier [19,20], the aldehydic signal in 1 H NMR studies is a very good indicator of the possible epimerization of this residue in aldehydic peptides containing three or more residues. No epimerization occurred during these reduction reactions.…”

Section: Resultsmentioning

confidence: 74%