The three‐dimensional solution structure of a constrained peptidomimetic in water and in chloroform observation of solvent induced hydrophobic cluster

Lee, Min S.; Gardner, Benjamin; Kahn, Michaël; Nakanishi, Hiroshi

doi:10.1016/0014-5793(95)00007-v

Cited by 8 publications

(3 citation statements)

References 59 publications

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“…An increase in the probability of forming one or both of these H-bonds in unbound cyclic peptides compared to unbound linear peptides may contribute to the higher affinities observed for the cyclic peptides. Cyclization has been shown to increase the propensity for /3-tum formation in peptides (Lee et al, 1995;Uma et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities

Giebel

Cass²,

Milligan³

et al. 1995

Biochemistry

196

171

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The screening of combinatorial peptide libraries has emerged as an important tool in the discovery of novel substrates or ligands for enzyme and receptor targets. For example, screening linear peptide libraries using streptavidin as a model receptor system has previously identified many low-affinity peptide ligands, all of which contain the common motif His-Pro-Gln (HPQ). We reasoned that constraining the conformational freedom of linear peptides by cyclization in a library would yield peptide ligands of increased affinity. Three different cyclic peptide libraries were constructed in an M13 phage display system as N-terminal pIII protein fusions. The random peptide sequences were flanked by two cysteine residues, which allows efficient disulfide bond formation and cyclization during phage assembly. These cyclic peptide libraries were screened with streptavidin as the model receptor system. Many sequences, all of which contained the motif His-Pro-Gln (HPQ), were discovered, and in the preceding paper, the structures of complexes of streptavidin-bound cyclic and linear peptides are described (Katz, 1995). Analysis of binding kinetics and affinities demonstrated that the conformationally constrained cyclic peptides bound streptavidin with affinities up to 3 orders of magnitude higher than linear peptides identified in previous library screens. These results demonstrate the potential of screening conformationally constrained peptide libraries for high-affinity novel receptor ligands or enzyme substrates.

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Section: Discussionmentioning

confidence: 99%

Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities

Giebel

Cass²,

Milligan³

et al. 1995

Biochemistry

196

171

View full text Add to dashboard Cite

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“…Although our experimental condition using CDCl 3 does not necessarily mimic the aqueous environment, there is a report indicating that the structural features of a 12-membered cyclic peptidomimetic with a similar size to bottromycin A 2 were retained in both water and chloroform. 23) Therefore, bottromycin A 2 could be expected to retain this interesting structural feature even in the aqueous environment. The thiazole ring of Thia-β-Ala-OMe(7) was found to be in close contact with Val(3), because several critical ROEs were observed between these two residues.…”

Section: )mentioning

confidence: 99%

Three-Dimensional Solution Structure of Bottromycin A2: A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

et al. 2012

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The three-dimensional (3D) structure of bottromycin A 2 , a natural anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococci (VRE) agent consisting of seven amino acids, has been investigated through NMR spectroscopy. On the basis of 57 experimental constraints, a total of 34 converged structures were obtained. The average pairwise atomic root mean square difference is 0.74 0.59 Å for all heavy atoms. The resulting structure indicates an interesting feature in that the three C-terminal residues of bottromycin A 2 fold back on the 12-membered cyclic skeleton made by the four N-terminal residues. Thus, MePro(2) and Thia-β-Ala-OMe(7), modification of which significantly affects the antibacterial activities of bottromycin A 2 , are located on one side of its 3D structure. These distinct structural features might be important for the binding of bottromycin A 2 with the bacterial ribosome.Key words bottromycin A 2 ; solution structure; NMR; antibiotic; methicillin-resistant Staphylococcus aureus; vancomycinresistant EnterococciThe increasing prevalence of multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) strains, has created serious problems worldwide.1,2) In particular, MRSA has been recognized as one of the major pathogens causing nosocomial infections. Therefore, there is an urgent and growing need for development of new antibiotics with novel modes of action to overcome the increasing threat posed by pathogens rapidly evolving drug resistance. During the screening for new types of anti-MRSA and anti-VRE agents from the natural product library in our institute, bottromycin A 2 was found to exhibit potent antibiotic activity against clinically-isolated MRSA and VRE strains, exhibiting minimum inhibitory concentration (MIC) values of 1.0 μg/mL and 0.5 μg/mL, respectively. 3)Bottromycin A 2 was first isolated from the fermentation broth of Streptomyces bottropensis by found to be an antibacterial peptide active against Grampositive bacteria and mycoplasma. [4][5][6][7][8] Bottromycin A 2 consists of seven amino acids, includes four unusual residues, and possesses a 12-membered cyclic skeleton made by the Gly(1)-tert-Leu(4) region (Fig. 1). The most significant structural characteristic is an amidine moiety formed through condensation of the cyclic tetrapeptide and linear tripeptide units. 9) As for the mode of action, bottromycin A 2 inhibits bacterial protein synthesis by blocking the binding of aminoacyl-tRNA to the A site on the 50S ribosome, but it does not inhibit peptide bond formation and translocation steps. [10][11][12] This function is different from that seen in the commonly used antibiotics, such as erythromycin and linezolid.13,14) Therefore, bottromycin A 2 represents a promising compound for development of novel antibiotics. Recently, we have accomplished the first asymmetric total synthesis and determination of the absolute stereochemistry of bottromycin A 2 .3) Ho...

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“…The increase in rigidity is an advantage that is translated into a decrease in the entropic term of Gibbs energy, improving binding affinities higher than some natural ligands to a biotarget [59][60][61][62]. Common motifs in the formation of proteins and polypeptides, β-turn, are other advantages of cyclization, as it is believed that this improves binding affinity [63][64][65]. Cyclization also allows the elimination of charged terminals at the ends of the structure in cyclic peptides, which may increase membrane permeability [66], although the peptide cross of the membrane does not improve just because the peptide is cyclized, but due to its structural features [67].…”

Section: Introductionmentioning

confidence: 99%

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

et al. 2022

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Oceans are a rich source of structurally unique bioactive compounds from the perspective of potential therapeutic agents. Marine peptides are a particularly interesting group of secondary metabolites because of their chemistry and wide range of biological activities. Among them, cyclic peptides exhibit a broad spectrum of antimicrobial activities, including against bacteria, protozoa, fungi, and viruses. Moreover, there are several examples of marine cyclic peptides revealing interesting antimicrobial activities against numerous drug-resistant bacteria and fungi, making these compounds a very promising resource in the search for novel antimicrobial agents to revert multidrug-resistance. This review summarizes 174 marine cyclic peptides with antibacterial, antifungal, antiparasitic, or antiviral properties. These natural products were categorized according to their sources—sponges, mollusks, crustaceans, crabs, marine bacteria, and fungi—and chemical structure—cyclic peptides and depsipeptides. The antimicrobial activities, including against drug-resistant microorganisms, unusual structural characteristics, and hits more advanced in (pre)clinical studies, are highlighted. Nocathiacins I–III (91–93), unnarmicins A (114) and C (115), sclerotides A (160) and B (161), and plitidepsin (174) can be highlighted considering not only their high antimicrobial potency in vitro, but also for their promising in vivo results. Marine cyclic peptides are also interesting models for molecular modifications and/or total synthesis to obtain more potent compounds, with improved properties and in higher quantity. Solid-phase Fmoc- and Boc-protection chemistry is the major synthetic strategy to obtain marine cyclic peptides with antimicrobial properties, and key examples are presented guiding microbiologist and medicinal chemists to the discovery of new antimicrobial drug candidates from marine sources.

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The three‐dimensional solution structure of a constrained peptidomimetic in water and in chloroform observation of solvent induced hydrophobic cluster

Cited by 8 publications

References 59 publications

Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities

Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities

Three-Dimensional Solution Structure of Bottromycin A2: A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

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