Diaminodiacid‐Based Solid‐Phase Synthesis of Peptide Disulfide Bond Mimics

Cui, Hongyang; Guo, Ye; He, Yao; Wang, Fengliang; Chang, Haonan; Wang, Yujia; Wu, Fangming; Tian, Changlin; Liu, Lei

doi:10.1002/anie.201302197

Cited by 128 publications

(43 citation statements)

References 53 publications

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“…Diaminodicarboxylic acid (DADC) building blocks x, y, and z ( Figure 7A) were synthesized according to literature and used for the synthesis of analogs 15 to 17 as described before. 27,44,45 Exemplarily, the synthesis strategy for thioether analog 16 (u 16 Table S2.…”

Section: The Disulfide Geometry Is Important For Activity and Am 1 mentioning

confidence: 99%

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation

Fischer

Schönauer

Els‐Heindl

et al. 2019

Journal of Peptide Science

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Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor‐like receptor (CLR), a class B G protein‐coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM‐1 receptor (AM1R). A disulfide‐bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t‐Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam‐based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether‐based mimetics to be well accepted with full AM1R activity. While a reduced selectivity over the calcitonin gene‐related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild–type‐like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.

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Section: The Disulfide Geometry Is Important For Activity and Am 1 mentioning

confidence: 99%

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation

Fischer

Schönauer

Els‐Heindl

et al. 2019

Journal of Peptide Science

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“…We first attempted to use the previous on‐resin DADA method to synthesize the Cys1‐Cys15 surrogate 2 . Linear precursor 5 incorporating a DADA building block was readily prepared, but its on‐resin cyclization yielded a complex mixture of products that included only a little of target product 2′ (Figure b).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Disulfide Surrogate Peptides Incorporating Large‐Span Surrogate Bridges Through a Native‐Chemical‐Ligation‐Assisted Diaminodiacid Strategy

Gao

et al. 2020

Angewandte Chemie

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The use of synthetic bridges as surrogates for disulfide bonds has emerged as a practical strategy to obviate the poor stability of some disulfide‐containing peptides. However, peptides incorporating large‐span synthetic bridges are still beyond the reach of existing methods. Herein, we report a native chemical ligation (NCL)‐assisted diaminodiacid (DADA) strategy that enables the robust generation of disulfide surrogate peptides incorporating surrogate bridges up to 50 amino acids in length. This strategy provides access to some highly desirable but otherwise impossible‐to‐obtain disulfide surrogates of bioactive peptide. The bioactivities and structures of the synthetic disulfide surrogates were verified by voltage clamp assays, NMR, and X‐ray crystallography; and stability studies established that the disulfide replacements effectively overcame the problems of disulfide reduction and scrambling that often plague these pharmacologically important peptides.

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“…Holland-Nell et al 11 used triazoles for replacement of the disulfide bonds in TPI I, and in another study, the biscarba diaminodiacids were used as the disulfide bond surrogate of TPI I. 12 The produced analogs maintained comparable or even had better antimicrobial activity than the native peptide.…”

Section: Introductionmentioning

confidence: 99%

Influences of disulfide connectivity on structure and antimicrobial activity of tachyplesin I

Shi

Chen

et al. 2018

Journal of Peptide Science

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Tachyplesin I is a potent antimicrobial peptide with broad spectrum of antimicrobial activity. It has 2 disulfide bonds and can form 3 disulfide bond isomers. In this study, the structure and antimicrobial activity of 3 tachyplesin I isomers (tachyplesin I, 3C12C, 3C7C) were investigated using molecular dynamic simulations, circular dichroism structural study, as well as antimicrobial activity and hemolysis assay. Our results suggest that in comparison to the native peptide, the 2 isomers (3C12C, 3C7C) have substantial structural and activity variations. The native peptide is in the ribbon conformation, while 3C12C and 3C7C possess remarkably different secondary structures, which are referred as "globular" and "beads" isomers, respectively. The substantially decreased hemolysis effects for these 2 isomers is accompanied by significantly decreased anti-gram-positive bacterial activity.

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Diaminodiacid‐Based Solid‐Phase Synthesis of Peptide Disulfide Bond Mimics

Cited by 128 publications

References 53 publications

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation

Synthesis of Disulfide Surrogate Peptides Incorporating Large‐Span Surrogate Bridges Through a Native‐Chemical‐Ligation‐Assisted Diaminodiacid Strategy

Influences of disulfide connectivity on structure and antimicrobial activity of tachyplesin I

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Diaminodiacid‐Based Solid‐Phase Synthesis of Peptide Disulfide Bond Mimics

Cited by 128 publications

References 53 publications

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation

Synthesis of Disulfide Surrogate Peptides Incorporating Large‐Span Surrogate Bridges Through a Native‐Chemical‐Ligation‐Assisted Diaminodiacid Strategy

Influences of disulfide connectivity on structure and antimicrobial activity of tachyplesin I

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Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM₁ receptor activation