Non-reducible disulfide bond replacement implies that disulfide exchange is not required for hepcidin–ferroportin interaction

Huang, Dong-Liang; Bai, Jingsi; Wu, Meng; Wang, Xia; Riedl, Bernd; Pook, Elisabeth; Alt, Carsten; Erny, Marion; Li, Yiming; Bierer, Donald; Shi, Jing; Fang, Ge‐Min

doi:10.1039/c9cc00328b

Cited by 7 publications

(4 citation statements)

References 35 publications

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“…In fact, while preventing Met oxidation during peptide resin cleavages has been thoroughly investigated, 40 Met oxidation during peptide synthesis has been less studied. 41 In fact, in some cases Met oxidation during synthesis can be so cumbersome, that a less oxidation-prone AA instead of Met is used, 42 and we thus set out to investigate the impact of hydroperoxides in NBP, as well as other SPPS solvents, on the oxidation of Met and other oxidizable AAs and peptides. To this end, we evaluated Met oxidation susceptibility in different solvents, determining the content of Fmoc-Met(O)-OH in Fmoc-Met-OH solutions over time (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

Pawlas,

El-Dine,

Bargen

et al. 2024

Org. Process Res. Dev.

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While numerous studies aimed at producing peptides in a sustainable manner have recently been reported, the impact of the quality of starting materials on sustainability in peptide synthesis has been less investigated. Here we report that NBP, a greener dipolar aprotic solvent suitable for use in SPPS, readily undergoes air oxidation to the corresponding hydroperoxide (NBP-OOH), which adversely affects oxidation-sensitive amino acids and peptides. Air, light, elevated temperatures, and common peptide synthesis reagents such as DIC accelerated the rate of NBP oxidation. LC-HRMS analyses revealed that air-induced NBP degradation proceeds via a different mechanism than the previously elucidated degradation of the closely related NMP while GC− MS of NBP containing NBP-OOH showed that standard GC-based analytical methods are unsuitable for NBP-OOH detection, warranting implementation of improved methods for NBP analyses. Assessment of NBP-OOH-induced Met, Trp, Cys, and Tyr breakdown revealed not only that NBP-OOH degrades all these oxidation-prone substrates, but it was also discovered that DITU, previously reported to suppress N-oxyl radical-induced peptide breakdown, constitutes an efficient suppressant of hydroperoxideinduced degradation. Studies on aerial oxidation of additional greener dipolar aprotic solvents DMSO and DMPU revealed that while the former is stable and does not cause oxidation, the latter is oxidized extensively upon air exposure and degrades oxidationprone substrates to a significant extent. On the other hand, air bubbling of NBP, DMSO, and DMPU proved to have an unexpected positive effect on the stability of the α-amino-bound Fmoc group, a finding that may be leveraged to minimize premature Fmoc loss during peptide synthesis. Overall, our studies on understanding and mitigating hydroperoxide formation in greener solvents for peptide synthesis illustrate the importance of a thorough quality assessment of starting materials during the development of sustainable synthetic methods.

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Section: Resultsmentioning

confidence: 99%

Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

Pawlas,

El-Dine,

Bargen

et al. 2024

Org. Process Res. Dev.

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“…The DADA-based disulfide replacement by non-reducible bridges was examined as a potential method to study this phenomenon between hepcidin and ferroportin. [22] Hepcidin is a 25-amino acid peptide containing four disulfide bonds and a key regulator of iron levels in mammals through attenuating the function of the iron transporter ferroportin. Previous studies concluded that the binding between ferroportin and hepcidin may or may not include an intermolecular disulfide exchange step.…”

Section: Hepcidin Analogs With Non-reducible Thioether Bondsmentioning

confidence: 99%

“…Previous studies concluded that the binding between ferroportin and hepcidin may or may not include an intermolecular disulfide exchange step. [22] To clarify this problem, a non-native hepcidin incorporating non-reducible CÀ S bonds in place of native SÀ S bond was synthesized using the DADA approach (Table 2). Four SÀ C bridged hepcidin disulfide surrogates (28, 29, 30, and 31) and four CÀ S bridged hepcidin disulfide surrogates (32, 33, 34, and 35) were synthesized using Allyl/Alloc protected CÀ S and SÀ C bridged diaminodiacids.…”

Section: Hepcidin Analogs With Non-reducible Thioether Bondsmentioning

confidence: 99%

A Diaminodiacid (DADA) Strategy for the Development of Disulfide Surrogate Peptides

Bierer

et al. 2020

Chemistry An Asian Journal

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Disulfide bond‐containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid‐phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA‐based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA‐based disulfide surrogates are described.

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“…In order to circumvent this issue, sulfur atoms have been substituted to replace one sulfur with carbon or oxygen or both sulfurs with carbon, through saturated or unsaturated bridges. The resulting peptide analogues are often comparable to the parent, ,,, with some having more prolonged or greater biological activity . This can be done using ring closing metathesis (RCM) of olefinic residues to create α-helical peptides that penetrate cells more efficiently than the natural peptides .…”

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confidence: 98%

Methylene Analogues of Neopetrosiamide as Potential Antimetastatic Agents: Solid-Supported Syntheses Using Diamino Diacids for Pre-Stapling of Peptides with Multiple Disulfides

et al. 2021

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Neopetrosiamide, a 28-residue peptide from Neopetrosia sp., contains three disulfide bonds and hinders mammalian tumor cell invasion. Proper connectivity of disulfide bonds is crucial for activity. Synthetic replacement of single disulfide bridges with methylene bridges gives active analogues. Pre-stapling of one ring enhances the correct formation of the remaining disulfides by reducing isomeric possibilities and possibly initiating the correct 3D fold. Cloning and expression of neopetrosiamide in E. coli affords access to the natural linear peptide.Letter pubs.acs.org/OrgLett

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Non-reducible disulfide bond replacement implies that disulfide exchange is not required for hepcidin–ferroportin interaction

Abstract: Non-reducible disulfide bond replacement was used to study the disculfide exchange between hepcidin and ferroportin, and the results indicate that the hepcidin–ferroportin interaction does not require disfulfide exchange.

Cited by 7 publications

References 35 publications

Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

A Diaminodiacid (DADA) Strategy for the Development of Disulfide Surrogate Peptides

Methylene Analogues of Neopetrosiamide as Potential Antimetastatic Agents: Solid-Supported Syntheses Using Diamino Diacids for Pre-Stapling of Peptides with Multiple Disulfides

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