Design of the Synthetic Route for Helical Peptides. Synthesis and Solubility of Model Peptides Having a Helical Structure

Abstract

Fragment condensations between amino- and carboxyl-components of hydrophobic decapeptides, which have a β-sheet structure in the solid state and are insoluble in DMF, NMP, and DMSO, were examined in a mixture of CH2Cl2 and TFE (4/1, v/v) using various coupling reagents. By the use of DCC and HOBt as coupling reagents, the reaction proceeded smoothly in moderate yield to give eicosapeptides. These have a stable helical structure in the solid state and are easily soluble in a variety of organic solvents. The hydrophobic eicosapeptides obtained were subjected to a successive coupling reaction in CH2Cl2 alone to give helical tetracontapeptides in high yield, which also have high solubility in various organic solvents of low polarity. The solubility of hydrophobic helical peptides presents a solubility feature of helical peptides which are obtained as peptide intermediates in protein synthesis. The synthetic strategy for helical peptides and proteins is discussed in connection with the solubility prediction method.

Role of α-Helix Conformation Cooperating with NH···S Hydrogen Bond in the Active Site of Cytochrome P-450 and Chloroperoxidase: Synthesis and Properties of [MIII(OEP)(Cys-Helical Peptide)] (M = Fe and Ga)

“…These models were designed to meet several criteria: (1) The peptides should form stable α-helix conformations in less polar solvent (THF, CH 2 Cl 2 , and CHCl 3 ) for characterization and synthesis of the Fe(III) and Ga(III) model complexes and the corresponding cysteinyl thiolate anion peptides. Our peptide design is based on the propensity of leucine residue to prefer high ability of helix formation , and solubility in organic solvents . (2) The peptides should contain the invariant fragments of P-450 and of CPO (Table ).…”

“…Our peptide design is based on the propensity of leucine residue to prefer high ability of helix formation 25,26 and solubility in organic solvents. 27 (2) The peptides should contain the invariant fragments of P-450 and of CPO (Table 1). As a P-450 model, an Ac-Leu-Cys-Leu-Ala fragment was introduced on the N terminus of the model peptide.…”

Solution‐Phase Peptide Synthesis

“…The low solubility of large segments brings about the low concentrations in the reaction mixtures, resulting in slow reaction rates. Narita et al reported that a mixture of chloroform (CHL) or DCM with HFIP, phenol, TFE, or some other polar solvent is an extremely good solvent for dissolving fully protected peptides [278]. One is the development of protecting groups, which can lead to peptide intermediates that are soluble in organic solvent systems that have high solubilizing potential.…”

Difficult Peptides

“…Based on previous observations of Narita et al that protected peptide segments in a random coil conformation are more soluble in organic solvent suitable DAEFRHDSGYEVHHQKLVFFAEDVGSNKG AIIGLMVGGVVIA [90] amyloidogenic neurotoxin prion peptide (106-126) KTNMKHMAGAAAAGAVVGGLG [91] acanthoscurrin (101-132) GGGLGGGRGGGYGGGGGYGGGYGGGYG GGKYK-NH 2 [35] Resin for aminoacylation conditions [82,83], Milton et al proposed a method that uses the Chou-Fasman conformational parameter P c (coil parameter for each amino acid) as follows: the average, <P c >, of a peptide segment reveals its tendency to assume a random coil conformation instead of a a-helix or b-sheet structure; consequently, <P c à > (P c à can be obtained from the linear regression of the function 1/P c ¼ 0.739P a þ 0.345P b ) values greater than 1.0 indicated easy coupling of the subsequent residue in an acceptable time; values in the range of 0.9-1.0 indicated a longer reaction time and need for recoupling; values lower than 0.9 indicated persistent difficult coupling [79]. The use of P a allowed for the preparation of aggregation profiles, such as those of acyl carrier protein (63-74), (Ala) 10 , cytochrome c (66-104), HIV-1 aspartyl protease (86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99), and growth hormone releasing factor , and for predicting potentially difficult couplings [93]. In 1993, Krchnak et al followed the volume changes of swollen peptide-resins during SPPS and derived a P a for each amino acid coupled (P a : aggregation potential, which reflects the propensity of the amino acid to contribute to peptide aggregation).…”