Dmab/ivDde protected diaminodiacids for solid-phase synthesis of peptide disulfide-bond mimics

The use of pre-prepared diaminodiacids has been established as an effective approach for the chemical synthesis of peptide disulfide bond mimics. A technical problem often encountered in the implementation of the diaminodiacids strategy is the use of heavy metal reagents to remove the side-chain protecting groups. In the present work, we reported the development of diaminodiacid that carry 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene)-3-methylbutyl]amino)benzyl (Dmab) and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) protecting groups. This pair of protecting groups can be readily removed by mild hydrazinolysis during the solid-phase synthesis on resin. We demonstrated the use of Dmab/ivDde protected diaminodiacids in the successful synthesis of a disulfide surrogate of oxytocin.     

Efficient synthesis of a side-chain extended diaminodiacid for solid-phase synthesis of peptide disulfide bond mimics

Solid-phase incorporation of diaminodiacids is one of the most effective approaches for synthesis of peptide disulfide bond mimics. One of a limitation of current diaminodiacid toolbox is that only four-atom linkage mimics are available that may not fully meet the activity optimization requirement. In this work, we developed a new diaminodiacid that contains a five-atom thioether (C–C–S–C–C) bridge for the first time. With this diaminodiacid in hand, we successfully obtained oxytocin containing new disulfide bond mimic by solid phase peptide synthesis.     

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

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.     

Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide‐Rich Peptides

Disulfide‐rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low‐yielding folding process. We found that a single cystine‐to‐diaminodiacid replacement could significantly increase the folding efficiency of disulfide‐rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the μ‐conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI‐II. NMR and X‐ray crystallography studies confirmed that these derivatives of disulfide‐rich peptide retained the correct three‐dimensional conformations. Moreover, the cystine‐to‐diaminodiacid replacement enabled structural tuning, thereby leading to an EETI‐II derivative with higher bioactivity than the native peptide.     

Single-Shot Solid-Phase Synthesis of Full-Length H2 Relaxin Disulfide Surrogates

Chemical synthesis of insulin superfamily proteins (ISPs) has recently been widely studied to develop next-generation drugs. Separate synthesis of multiple peptide fragments and tedious chain-to-chain folding are usually encountered in these studies, limiting accessibility to ISP derivatives. Here we report the finding that insulin superfamily proteins (e.g. H2 relaxin, insulin itself, and H3 relaxin) incorporating a pre-made diaminodiacid bridge at A-B chain terminal disulfide can be easily and rapidly synthesized by a single-shot automated solid-phase synthesis and expedient one-step folding. Our new H2 relaxin analogues exhibit almost identical structures and activities when compared to their natural counterparts. This new synthetic strategy will expediate production of new ISP analogues for pharmaceutical studies.     

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

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.     

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

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.     

Synthesis of a chlorothalonil peptide conjugate mimicking protein-bound pesticide residues

A strategy for the synthesis of model conjugates resembling protein-bound pesticide residues was developed on the instance of the fungicide chlorothalonil. Starting from a synthetic dodecapeptide with Fmoc and ivDde protecting groups, a multistep procedure was established for the synthesis of a defined structure.     

Solid-phase synthesis of disulfide heterodimers of peptides

[structure: see text] The synthesis of the orthogonal disulfide template 1 and its use to synthesize unsymmetrical intermolecular disulfide bond peptides on a solid support are described. Application of template 1 to synthesize bioconjugates of cell permeable moieties based on the disulfide bond is demonstrated.     

Diaminodiacid bridge improves enzymatic and in vivo inhibitory activity of peptide CPI-1 against botulinum toxin serotype A

The replacement of the disulfide bridge of CPI-1, a peptide inhibitor of light chain of Botulinum toxin serotype A, with the thioether-containing and biscarba-containing diaminodiacid bridge leads to a significant decrease in the degradation by trypsin and increase in the detoxification activity in vivo, the addition of hydrophobic or positive amino acid at C-terminus of modified peptides further improves the inhibitory activity.     

Chemical synthesis and biological activity of peptides incorporating an ether bridge as a surrogate for a disulfide bond

Disulfide bridges contribute to the definition and rigidity of polypeptides, but they are inherently unstable in reducing environments and in the presence of isomerases and nucleophiles. Strategies to address these deficiencies, ideally without significantly perturbing the structure of the polypeptide, would be of great interest. One possible surrogate for the disulfide bridge is a simple thioether, but these are susceptible to oxidation. We report the introduction of an ether linkage into the biologically active, disulfide-rich peptides oxytocin, tachyplesin I, and conotoxin α-ImI, using an ether-containing diaminodiacid as the key building block, obtained by the stereoselective ring-opening addition reaction of an aziridine skeleton with a hydroxy group. NMR studies indicated that the derivatives with an ether surrogate bridge exhibited very small change of their three-dimensional structures. The analogs obtained using this novel substitution strategy were found to be more stable than the original peptide in oxidative and reductive conditions; without a loss of bioactivity. This strategy is therefore proposed as a practical and versatile solution to the stability problems associated with cysteine-rich peptides.

We report the first introduction of an ether linkage as surrogate into the disulfide-rich peptides using ether-containing diaminodiacid.     

Solid-phase synthesis of a type II′ β-turn peptido-mimetic library

The solid-phase synthesis of a dipeptide derived 2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carboxylate system (IBTM) is described. The IBTM moiety is formed via a solid-phase mediated Pictet-Spengler reaction of N-terminal tryptophan and the 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl (Dmab) ester of Fmoc protected aspartic acid β-aldehyde followed by γ-lactamization. This synthesis allows the regio- and stereoselective incorporation of a dipeptide surrogate of type II′ β-turns. The procedure is easily adaptable to combinatorial synthesis and a 576-member library was synthesized.     

Palladium‐Mediated Direct Disulfide Bond Formation in Proteins Containing S‐Acetamidomethyl‐cysteine under Aqueous Conditions

One of the applied synthetic strategies for correct disulfide bond formation relies on the use of orthogonal Cys protecting groups. This approach requires purification before and after the deprotection steps, which prolongs the entire synthetic process and lowers the yield of the reaction. A major challenge in using this approach is to be able to apply one‐pot synthesis under mild conditions and aqueous media. In this study, we report the development of an approach for rapid disulfide bond formation by employing palladium chemistry and S‐acetamidomethyl‐cysteine [Cys(Acm)]. Oxidation of Cys(Acm) to the corresponding disulfide bond is achieved within minutes in a one‐pot operation by applying palladium and diethyldithiocarbamate. The utility of this reaction was demonstrated by the synthesis of the peptide oxytocin and the first total chemical synthesis of the protein thioredoxin‐1. Our investigation revealed a critical role of the Acm protecting group in the disulfide bond formation, apparently due to the generation of a disulfiram in the reaction pathway, which significantly assists the oxidation step.     

The Synthesis of a 2D Ultra-Large Protein Supramolecular Nanofilm by Chemoselective Thiol–Disulfide Exchange and its Emergent Functions

The design and scalable synthesis of robust 2D biological ultrathin films with a tunable structure and function and the ability to be easily transferred to a range of substrates remain key challenges in chemistry and materials science. Herein, we report the use of the thiol–disulfide exchange reaction in the synthesis of a macroscopic 2D ultrathin proteinaceous film with the potential for large-scale fabrication and on-demand encapsulation/release of functional molecules. The reaction between the Cys6–Cys127 disulfide bond of lysozyme and cysteine is chemo- and site-selective. The partially unfolded lysozyme–cysteine monomers aggregate at the air/water or solid/liquid interface to form an ultra-large 2D nanofilm (900 cm²) with about 100 % optical transparency. This material adheres to a wide range of substrates and encapsulates and releases a range of molecules without significantly affecting activity.     

The Synthesis of a 2D Ultra‐Large Protein Supramolecular Nanofilm by Chemoselective Thiol–Disulfide Exchange and its Emergent Functions

The design and scalable synthesis of robust 2D biological ultrathin films with a tunable structure and function and the ability to be easily transferred to a range of substrates remain key challenges in chemistry and materials science. Herein, we report the use of the thiol–disulfide exchange reaction in the synthesis of a macroscopic 2D ultrathin proteinaceous film with the potential for large‐scale fabrication and on‐demand encapsulation/release of functional molecules. The reaction between the Cys6–Cys127 disulfide bond of lysozyme and cysteine is chemo‐ and site‐selective. The partially unfolded lysozyme–cysteine monomers aggregate at the air/water or solid/liquid interface to form an ultra‐large 2D nanofilm (900 cm²) with about 100 % optical transparency. This material adheres to a wide range of substrates and encapsulates and releases a range of molecules without significantly affecting activity.     

Synthesis of Dithiocarbamates Containing Disulfide Linkage Using Cyclic Trithiocarbonate and Amines under Solvent–Catalyst Free Condition

A green and facile synthesis of dithiocarbamate derivatives containing disulfide linkage by the ring opening reaction of trithiocarbonate with amines under solvent and catalyst‐free condition with excellent yields is being reported. Environmental benignity, easy work up, smaller reaction time, and lack of column chromatography are the significant features of this protocol. The cyclic trithiocarbonate ( 1 ) has been used as a starting material for the first time to synthesize compounds of biological interest ( 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j , 3k , 3l , 3m , 3n , 3o , 3p , 3q ).     

A novel ring opening reaction of peptide N-terminal thiazolidine with 2,2′-dipyridyl disulfide (DPDS) efficient for protein chemical synthesis

In the protein chemical synthesis via native chemical ligation (NCL) method with three peptide segments, the N-terminal cysteine residue of middle segment is generally protected by thiazolidine ring. In this paper, we show the novel method for thiazolidine ring opening using 2,2′-dipyridyl disulfide (DPDS). The N-terminal thiazolidine was converted into S-pyridylsulfenylated cysteine residue with DPDS under acidic conditions, and this N-terminally Cys peptide protected with disulfide was applicable to NCL reaction without purification and deprotection steps. DPDS treatment did not remove other Cys protecting groups generally used for regioselective disulfide bond formation reactions. These results indicate that this thiazolidine ring opening reaction is quite useful for the protein chemical synthesis with three-segment NCL strategy.     

Fe-Zn-Zr/分子筛复合催化剂上CO2加氢合成异构烷烃Ⅰ.不同分子筛对催化剂性能的影响

 在Fe-Zn-Zr/分子筛复合催化剂上考察了不同类型的分子筛对CO2加氢反应性能的影响. 结果表明,不同分子筛对复合催化剂性能的影响不同,Fe-Zn-Zr/HY是合成异构烷烃有效的复合催化剂. 分子筛的酸性及酸强度对复合催化剂性能有较大的影响,中等强度和较高强度的酸性位有利于异构烃的生成.     

Dual Temperature and Thiol‐Responsive POEOMA‐Multisegmented Polydisulfides: Synthesis and Thermoresponsive Properties

New thermoresponsive polydisulfides of POEOMA multiblocks linked with disulfide bonds having redox‐responsive properties are reported. These POEOMA‐multisegmented polydisulfides were synthesized by a new method employing a combined RAFT/aminolysis and reversible thiol‐disulfide redox reaction that centers on the synthesis of new disulfide‐labeled difunctional RAFT agent. RAFT polymerization proceeded in living fashion, yielding well‐defined POEOMA copolymers with middle disulfides and terminal RAFT species. They were then used as precursors for thiol‐disulfide polyexchange induced by aminolysis and reductive reaction followed by oxidation: these polydisulfides with different molecular weights and end groups ex hibited tunable thermoresponsive properties and thiol‐responsive degradation.     

Ultrasmall Cu7S4@MoS2 Hetero‐Nanoframes with Abundant Active Edge Sites for Ultrahigh‐Performance Hydrogen Evolution

Increasing the active edge sites of molybdenum disulfide (MoS₂) is an efficient strategy to improve the overall activity of MoS₂ for the hydrogen‐evolution reaction (HER). Herein, we report a strategy to synthesize the ultrasmall donut‐shaped Cu₇S₄@MoS₂ hetero‐nanoframes with abundant active MoS₂ edge sites as alternatives to platinum (Pt) as efficient HER electrocatalysts. These nanoframes demonstrate an ultrahigh activity with 200 mA cm^?2 current density at only 206 mV overpotential using a carbon‐rod counter electrode. The finding may provide guidelines for the design and synthesis of efficient and non‐precious chalcogenide nanoframe catalysts.