Diastereomeric Selective Effects for Growth Inhibition of Synthesized Mini Parallel Double-Stranded Peptides on Escherichia coli and Staphylococcus aureus

Abstract

The function of proteins and enzymes is much related to the tertiary structure formed with the folding of secondary structures, e.g., the a-helix, b-sheet, or b-turn. Although bsheet or b-turn structures are found in peptides and proteins, their biological functions are poorly understood yet compared with the a-helix. In an effort to clarify the chemical properties, functions, and stereochemistry of b-turn (or bhairpin) and antiparallel b-sheet structures, the design and synthesis of peptides have been reported by a number of research groups. [1][2][3][4][5][6] Model compounds which mimic b-sheet and b-turn structures have been shown to adopt b-hairpin structures in an aqueous solution, and hydrogen bonding can stabilize the b-turn structure. Recently, we have reported the synthesis and chemical properties of mini parallel doublestranded peptides, (L-AA 3 -L-AA 2 -L-AA 1 ) 2 -spacer(S) (AAϭ amino acids; Sϭethano-and dodecano-, etc.) conjugated two peptide strands to a mini loop (ϭspacer).-diamine mediated b-sheet-like conformation were described in the previous paper because the sequences like -Phe-Phe-, -Leu-Phe-Phe-, and -Val-Phe-Phe-which are little existence in natural peptides and proteins. Moreover, the -Val-Phe-Phe-, interestingly, is contained in Alzheimer's disease related b-amyloid peptide (Ab).The aims of the present study are the synthesis of doublestranded peptides containing chiral -x-Phe-y-Phe-sequences and elucidation of the structure-activity relationship between antibacterial activity and chirality of the -Phe-Phesequence. We synthesized four chiral types Showa Phamaceutical University; 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan. Received September 8, 2003; accepted November 7, 2003 The synthesis of a series of mini double-stranded peptides containing chiral-x-Phe-y-Phe-peptide residues and the diastereomeric selective effects of these compounds on Escherichia coli NIHJ JC-2 and Staphylococcus aureus FDA 209P

Diastereomeric Selective Effects of Double-Stranded Peptides Conjugated with &ndash;Phe&ndash;Phe&ndash; Residue for Growth Inhibition and Permeability of Ca²⁺ on A431, <i>src</i>^tsNRK, and A549 Cells Proliferation

“…In a previously published study, we designed and synthesized parallel double-stranded peptides (1), bis(z-Phey-Phe-x-Val) 2 -spacer(S) and bis(y-Phe-x-Phe) 2 -spacer(S) (symbols x, y and zϭL-or D-configurations, AAϭamino acid, Sϭspacer, and Pheϭphenylalanine), conjugated with two -Val-Phe-Phe-and -Phe-Phe-peptide residues, respectively, to a polyamine spacer. 1,2) The -Val-Phe-Phe-and -Phe-Phe-sequences are p-electron rich and in hydrophobic sequence, and the appearance rate is low in the natural proteins.…”

“…1,2) The -Val-Phe-Phe-and -Phe-Phe-sequences are p-electron rich and in hydrophobic sequence, and the appearance rate is low in the natural proteins. For example, the appearance rates of the -Phe-Pheand -Val-Phe-Phe-sequences in a human progesterone receptor form B (hPR; 933AA (AAϭamino acid) 3) ) were 0%.…”

“…The introduction of p-electron rich and a hydrophobic side chain in the doublestranded peptides can have a role of molecular inclusion and recognition by interaction between the double-stranded peptide and the target. 1) In addition, four optical isomers, (L-, L-), (D-, L-), (L-, D-), and (D-, D-), to bis(y-Phe-x-Phe) 2 -spacer(S) are possible in the synthesis and we synthesized them.…”

“…Especially, the anti-proliferative effects on tumor cells of the diastereomers are poorly understood when compared with that of the enantiomer. Here, our aim in this study is to understand better the structure-activity relationships between cell anti-proliferative effects and four optical isomers of the classes of bis(y-Phe-x-Phe) 2 -spacer(S). We found that the bis(y-Phex-Phe) 2 -spacer(S)s are very valuable for investigating the anti-proliferative effect of tumor cells since the evidence for the configurational pattern of the compound-target cell interaction on cell death is lacking.…”

“…Because the double-stranded peptides interact with the cell membrane and may play an important role in the transportation of polyamines, 10) Na ϩ , and Ca 2ϩ ions into cells. In order to understand the role of the chilarity of bis(y-Phe-xPhe) 2 -spacer(S) on cell growth inhibition, the change in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ) was measured by fluorometry using Fura-2.…”