IBTM-Containing Gramicidin S Analogues:  Evidence for IBTM as a Suitable Type II‘ β-Turn Mimetic1,2

Andreu, David; Ruiz, Aurora; Carreño, Ana; Alsina, A.; Alberício, Fernando; Jímenez, Bernat; Figuera, c Natalia de la; Herranz, Carmen; García-López, c and María Teresa; c, Rosario González-Muñiz

doi:10.1021/ja9705755

Cited by 54 publications

(52 citation statements)

References 29 publications

(32 reference statements)

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“…[90] This may be briefly illustrated for b-turn mimics: [91] A b-turn is a folding motif of a peptide chain, in which the chain direction is reversed in space to allow the formation of b-sheets. When designing b-turn mimics, one concentrates on rigid analogues, like 73, [92] or ones of limited conformational mobility, such as 74 [93] or 75 [94] (Scheme 36).…”

Section: Applications Of Conformation Designmentioning

confidence: 99%

Conformation Design of Open-Chain Compounds

Hoffmann

2000

Angew. Chem. Int. Ed.

239

173

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At the brink of the 21st century, chemistry is increasingly concerned with the function that molecules fulfil as drugs, receptors, or—as ensemble of molecules—as materials. The capability of compounds to fulfil such functions cannot sufficiently be described by using only the terms composition and configuration. A decisive role is played in addition by the conformation of the molecules, which serves as the link between molecular composition and molecular function. Expressions such as “active conformation” or “competent conformation” allude to this aspect. Chemists have to develop an understanding how a flexible molecule adopts the conformation (a distinct shape) which is optimal for the function in question and how this process can be controlled. On the outset of such considerations, we may ask how nature succeeded in the process of evolution to endow flexible molecules with a preference to adopt the conformation which is optimal for the function it has to serve. In this review, I report on how we have reached a crude level of understanding of conformation design in nature with reference to the class of polyketide natural products, how we developed these insights into a conformation design of open‐chain compounds, and which applications are already in sight.

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Section: Applications Of Conformation Designmentioning

confidence: 99%

Conformation Design of Open-Chain Compounds

Hoffmann

2000

Angew. Chem. Int. Ed.

239

173

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“…GS adopted a C 2 ‐symmetric antiparallel β‐sheet with two type II′ β‐turns at the d ‐Phe‐Pro sequences . Several GS analogs, which contained thioindolizines, indolizines, sugar amino acids and their homologs, d ‐Pro‐Phe, morpholine amino acids, or di‐γ‐peptide at the d ‐Phe‐Pro sequence, have been studied with the aim of designing potent antimicrobial agents …”

Section: Resultsmentioning

confidence: 99%

Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

Kang

Park

2015

Biopolymers

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Conformational preferences for the turn and β-hairpin structures of Ala-based peptides [Ac-Ala(n)-(R)-Nip-(S)-Nip-Ala(n)-X (n = 0-2; X = NHMe or NMe2)] containing nipecotic acid (Nip) residues were carried out using the density functional M06-2X and the implicit solvation model SMD in CH2Cl2 and/or water. The turn structure of the (R)-Nip-(S)-Nip segment with a C10 H-bond between two terminal groups was found to be most preferred (populated at 98.9%) in CH2Cl2; this structure is consistent with IR and (1)H NMR results. The stabilities of the β-hairpins containing the (R)-Nip-(S)-Nip segment as a turn motif relative to the extended structures increased with peptide sequence length. The relative strengths of the H-bonds between the carbonyl oxygen and the amide hydrogen appeared to be responsible for stabilizing the turn and β-hairpin structures in CH2Cl2. In addition, the (R)-Nip-(S)-Nip segment exhibited the capability to be incorporated into one of the two β-turn motifs of gramicidin S (GS). The structure of this GS derivative (GS-Nip2 ) was generally similar to the native peptide but was less hydrophobic and it is therefore expected to exhibit lower hemolytic activity; however, further experiments are needed to evaluate its antimicrobial activity. The structure of GS-Nip2 was somewhat more flexible than GS in solvents of higher polarity. Thus, our calculated results regarding the turn and β-hairpin motifs of the (R)-Nip-(S)-Nip segment indicate that this structure might be useful for the design of bioactive macrocyclic peptides containing β-hairpin mimics as well as binding epitopes in protein-protein and protein-nucleic acid recognitions.

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“…Turns may or may not be stabilized by an intramolecular hydrogen bond between the CO group of residue i and the i+4 (α), or i+3 (β), or i+2 (γ) amide NH. Due to their structural simplicity, we and other groups started extensive research programs aimed at developing secondary structure peptidomimetics of these non-repetitive motifs, specially β-turns [38][39][40][41][42][43][44][45][46]. Several general reviews provide interesting overviews on amino acid derivatives and peptide-derived scaffolds that, when incorporated into peptide sequences could induce or force the adoption of turn-like conformations [47][48][49][50][51][52][53][54][55].…”

Section: Approaches To Generate Stabilized Reverse Turnsmentioning

confidence: 99%

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Vega

Martı́n-Martı́nez²,

González‐Muñiz

2007

CTMC

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In view of the crucial role of protein-protein intercommunication both in biological and pathological processes, the search of modulators of protein-protein interactions (PPIs) is currently a challenging issue. The development of rational strategies to imitate key secondary structure elements of protein interfaces is complementary to other approaches based on the screening of synthetic or virtual libraries. In this sense, the present review provides representative examples of compounds that are able to disturb PPIs of therapeutic relevance, through the stabilization or the imitation of peptide hot-spots detected in contact areas of the interacting proteins. The review is divided into three sections, covering mimetics of the three main secondary structural elements found in proteins, in general, and in protein-protein interfaces, in particular (alpha-helices, beta-sheets, and reverse turns). Once the secondary element has been identified, the first approach typically involves the translation of the primary peptide structure into different cyclic analogues. This is normally followed by gradual decrease of the peptide nature through combination of peptide and non-peptide fragments in the same molecule. The final step usually consists in the development of pertinent organic scaffolds for appending key functional groups in the right spatial disposition, as a means towards totally non-peptide small molecule PPI modulators.

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IBTM-Containing Gramicidin S Analogues: Evidence for IBTM as a Suitable Type II‘ β-Turn Mimetic¹^,²

Cited by 54 publications

References 29 publications

Conformation Design of Open-Chain Compounds

Conformation Design of Open-Chain Compounds

Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

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