Studies on cyclic peptides. II. Synthesis of cyclic peptides containing sarcosine

Sugihara, Toshiharu; Imanishi, Yukio; Higashimura, Toshinobu

doi:10.1002/bip.1975.360140405

Cited by 12 publications

(7 citation statements)

References 10 publications

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“…Sugihara et al 5 have synthesized a series of cyclic hexapeptides containing the sarcosine residue and revealed a relationship between the conformational multiplicity and the ease of complexation with metal cations. It was demonstrated that the moderate flexibility imparted by the sarcosine residue of a cyclic peptide is one of the important factors involved in ion binding.…”

Section: Introductionmentioning

confidence: 98%

Cation binding cyclic peptides composed of imino acid residues

Shimizu

Fujishige

1980

Biopolymers

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SynopsisCyclo(L-Pro-Sar), (n = 2-4) with moderate flexibility and hydrophobicity of molecular structure was synthesized, and the characteristics of these cyclic peptides and their metal complexes in acetonitrile were investigated in connection with the residual properties using 13C-nmr measurements. The cyclic tetrapeptide cyclo(~-Pro-Sar)z showed a sterically hindered phenomenon in acetonitrile in which the amide backbone adopted a cis-trans-cis-trans sequence. The cyclic hexapeptide cyclo(~-Pro-Sar)~ existed as a mixture of several conformers whose interconversion is slow on the nmr time scale, including cis-cis-trans and/or cistrans-trans arrangement of the Sar-Pro bond. Finally, it was demonstrated that the cyclic octapeptide cyclo(L-Pro-Sar)4 behaved as a mixture of multiple conformers which allowed for cis-trans isomerism about the Pro-Sar peptide bond, of which 20-30% had the all-cis Sar-Pro bond isomer and the remaining 7040% had one (or more) cis Sar-Pro bond isomer. 13C-nmr spectra also demonstrated that cyclo(L-Pro-Sar), (n = 3,4) formed a 1:l ion complex whose conformation was characterized by an all-trans peptide bond in the presence of excess metal salt. Cation binding studies, using CD measurements, established that the ion selectivity of cyclo(L-Pro-Sar)4 in acetonitrile decreased in the order, Ba2+ > Ca2+ > Na+ > Mg2+ > Li+.

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Section: Introductionmentioning

confidence: 98%

Cation binding cyclic peptides composed of imino acid residues

Shimizu

Fujishige

1980

Biopolymers

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“…The tag consisting of three consecutive Sar residues is capped with an acetyl-Ala group to maintain a neutral peptide N-terminus. The Sar tag was omitted from TM8, because C-terminal Sar tags are known to greatly reduce synthesis yields . An additional modification for ease of handling was to exchange the endogenous Cys residues in TM8 for the isostere α-aminobutyric acid (Abu) to avoid unwanted cross-linking …”

Section: Resultsmentioning

confidence: 99%

Peptide-Based Approach to Inhibition of the Multidrug Resistance Efflux Pump AcrB

et al. 2020

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Clinically relevant multidrug-resistant bacteria often arise due to overproduction of membrane-embedded efflux proteins that are capable of pumping antibiotics out of the bacterial cell before the drugs can exert their intended toxic effect. The Escherichia coli membrane protein AcrB is the archetypal protein utilized for bacterial efflux study because it can extrude a diverse range of antibiotic substrates and has close homologues in many Gram-negative pathogens. Three AcrB subunits, each of which contains 12 transmembrane (TM) helices, are known to trimerize to form the minimal functional unit, stabilized noncovalently by helix−helix interactions between TM1 and TM8. To inhibit the efflux activity of AcrB, we have rationally designed synthetic peptides aimed at destabilizing the AcrB trimerization interface by outcompeting the subunit interaction sites within the membrane. Here we report that peptides mimicking TM1 or TM8, with flanking N-terminal peptoid tags, and C-terminal lysine tags that aid in directing the peptides to their membrane-embedded target, decrease the AcrBmediated efflux of the fluorescent substrate Nile red and potentiate the effect of the antimicrobials chloramphenicol and ethidium bromide. To further characterize the motif encompassing the interaction between TM1 and TM8, we used Forster resonance energy transfer to demonstrate dimerization. Using the TM1 and TM8 peptides, in conjunction with several selected mutant peptides, we highlight residues that may increase the potency and specificity of the peptide drug candidates. In targeting membrane-embedded protein−protein interactions, this work represents a novel approach to AcrB inhibition and, more broadly, a potential route to a new category of efflux pump inhibitors.

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“…On the other hand, the addition of benzene to the chloroform solution of Cyclo-(Sar2) and Cyclo-(Sar-Gly) caused upfield shifts of N.CH 3 and C~H2 resonance signals (71), although these cyclic peptides only have a cis peptide bond. The upfield shift implies the complex formation between the cyclic peptides and benzene.…”

Section: Dipole Interactions Of Cyclic Peptides With Aromatic Compoundsmentioning

confidence: 98%

“…The present author has synthesized a number of cyclic peptides containing imino acid residues such as Cyclo-(Sar2), Cyclo-(Sar-Gly), Cyclo-(Sar4) , Cyclo-(Sar6) , Cyclo-(Sar-Sar-Gly)2, Cyclo-(Pro-Sar-GlY)2, and Cyclo-(Sar-Gly-Gly)2. For example, the syntheses (20) otherwise stated. The C-terminal was protected by a benzyl ester group, which minimizes the conversion of the peptides containing imino acid residues into a diketopiperazine derivative in the presence of acid or alkali (21)(22)(23).…”

Section: Synthesis Of Cyclic Peptidesmentioning

confidence: 99%

“…If this relationship also holds for the interactions of benzene with other cyclic peptides containing N-substituted amino acid, the conformation of the peptide bond can be determined on the basis of the benzene-induced shift. According to this consideration, Cyclo-(Pro-Sar-Gly)2 was synthesized and its conformation was analyzed (71). The details are described in Section 3.8.…”

Section: Dipole Interactions Of Cyclic Peptides With Aromatic Compoundsmentioning

Studies on cyclic peptides. II. Synthesis of cyclic peptides containing sarcosine

Cited by 12 publications

References 10 publications

Cation binding cyclic peptides composed of imino acid residues

Cation binding cyclic peptides composed of imino acid residues

Peptide-Based Approach to Inhibition of the Multidrug Resistance Efflux Pump AcrB

Syntheses, conformation, and reactions of cyclic peptides

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