Synthetic relaxins

Hossain, Mohammed Akhter; Wade, John D.

doi:10.1016/j.cbpa.2014.09.014

Cited by 48 publications

(35 citation statements)

References 43 publications

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“…Although the chain combination method works well in the case of native insulin, a satisfactory yield of relaxin initially could not be obtained because of poor solubility of the B‐chain. This problem was minimized by the addition of organic solvents or other denaturing reagents to the folding buffer, presumably disrupting aggregation of the B‐chain . Truncation (1–25) or extension (1–33) of the B‐chain was also noted to enhance its solubility and increase chain combination yield without impacting biological activity .…”

Section: The Chemical Synthesis Of Relaxin and Insulin‐like Peptidesmentioning

confidence: 99%

Chemical synthesis of peptides within the insulin superfamily

Liu

Zaykov

Levy

et al. 2016

Journal of Peptide Science

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The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this centrally important metabolic hormone. This review highlights milestones in the chemical synthesis of insulin that can be divided into two separate approaches: (i) disulfide bond formation driven by protein folding and (ii) chemical reactivity-directed sequential disulfide bond formation. Common to the two approaches are the persistent challenges presented by the hydrophobic nature of the individual A-chain and B-chain and the need for selective disulfide formation under mildly oxidative conditions. The extension and elaboration of these synthetic approaches have been ongoing within the broader insulin superfamily. These structurally similar peptides include the insulin-like growth factors and also the related peptides such as relaxin that signal through G-protein-coupled receptors. After a half-century of advances in insulin chemistry, we have reached a point where synthesis is no longer limiting structural and biological investigation within this family of peptide hormones. The future will increasingly focus on the refinement of structure to meet medicinal purposes that have long been pursued, such as the development of a glucose-sensitive insulin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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Section: The Chemical Synthesis Of Relaxin and Insulin‐like Peptidesmentioning

confidence: 99%

Chemical synthesis of peptides within the insulin superfamily

Liu

Zaykov

Levy

et al. 2016

Journal of Peptide Science

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“…Our laboratory has developed efficient protocols that exploit the availability of cysteine S-thiol protecting groups that are orthogonal to one another and which allows the sequential, directed disulfide bond formation of separately assembled A- and B-chains (Scheme 1) [21] . These have enabled the successful preparation of many INSLs ranging from relaxins of different species to human INSLs3-5 and their analogues [22–25] .…”

Section: Resultsmentioning

confidence: 99%

Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2)

et al. 2017

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In the fruit fly Drosophila melanogaster, there are eight insulin-like peptides (DILPs) with DILPs 1-7 interacting with a sole insulin-like receptor tyrosine kinase (DInR) while DILP8 interacts with a single G protein-coupled receptor (GPCR), Lgr3. Loss-of-function dilp mutation studies show that the neuropeptide DILP2 has a key role in carbohydrate and lipid metabolism as well as longevity and reproduction. A better understanding of the processes whereby DILP2 mediates its specific actions is required. Consequently we undertook to prepare DILP2 as part of a larger, detailed structure-function relationship study. Use of our well-established insulin-like peptide synthesis protocol that entails separate solid phase assembly of each of the A- and B-chains with selective cysteine S-protection followed by sequential S-deprotection and simultaneous disulfide bond formation produced DILP2 in good overall yield and high purity. The synthetic DILP2 was shown to induce significant DInR phosphorylation and downstream signalling, with it being more potent than human insulin. This peptide will be a valuable tool to provide further insights into its binding to the insulin receptor, the subsequent cell signalling and role in insect metabolism.

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“…Relaxin family is a group of peptide hormones, including relaxin (primates have two relaxin genes), relaxin-3, and insulin-like peptide 3–6 (INSL3-6) 1–5 . These peptides perform a variety of biological functions 1–5 , such as regulating reproduction, food intake, stress responses, and glucose homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…These peptides perform a variety of biological functions 1–5 , such as regulating reproduction, food intake, stress responses, and glucose homeostasis. To date, four formerly orphan G protein-coupled receptors (GPCRs) have been identified as their receptors and renamed relaxin family peptide receptor 1–4 (RXFP1–4).…”

Section: Introductionmentioning

confidence: 99%

Development of a selective agonist for relaxin family peptide receptor 3

Wei

Shao

et al. 2017

Sci Rep

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Relaxin family peptides perform a variety of biological functions by activating four G protein-coupled receptors, namely RXFP1–4. Among these receptors, RXFP3 lacks a specific natural or synthetic agonist at present. A previously designed chimeric R3/I5 peptide, consisting of the B-chain of relaxin-3 and the A-chain of INSL5, displays equal activity towards the homologous RXFP3 and RXFP4. To increase its selectivity towards RXFP3, in the present study we conducted extensive mutagenesis around the B-chain C-terminal region of R3/I5. Decreasing or increasing the peptide length around the B23–B25 position dramatically lowered the activation potency of R3/I5 towards both RXFP3 and RXFP4. Substitution of B23Gly with Ala or Ser converted R3/I5 from an efficient agonist to a strong antagonist for RXFP3, but the mutants retained considerable activation potency towards RXFP4. Substitution of B24Gly increased the selectivity of R3/I5 towards RXFP3 over the homologous RXFP4. The best mutant, [G(B24)S]R3/I5, displayed 20-fold higher activation potency towards RXFP3 than towards RXFP4, meanwhile retained full activation potency at RXFP3. Thus, [G(B24)S]R3/I5 is the best RXFP3-selective agonist known to date. It is a valuable tool for investigating the physiological functions of RXFP3, and also a suitable template for developing RXFP3-specific agonists in future.

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Synthetic relaxins

Cited by 48 publications

References 43 publications

Chemical synthesis of peptides within the insulin superfamily

Chemical synthesis of peptides within the insulin superfamily

Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2)

Development of a selective agonist for relaxin family peptide receptor 3

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