Peptide Science最新文献

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Effective cell penetration of negatively‐charged proline‐rich SAP(E) peptides with cysteine mutation 半胱氨酸突变的带负电荷富含脯氨酸的SAP（E）肽的有效细胞穿透

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-12-09 DOI: 10.1002/pep2.24301

Sewon Lim, Jinhyuk Park, Seung‐Eun Chong, Sungwhan Kim, Yoonhwa Choi, Sohee Nam, Yan Lee

Most of cell penetrating peptides (CPPs) are rich in positively‐charged amino acids but the cationic property may provoke possible problems in practical applications. In this study, we carefully substituted the hydrophobic amino acids in the SAP(E) sequence, a rare example of negatively‐charged proline‐rich CPP, with cysteine for enhancement of cell penetrating activity as well as reversible conjugation of cargo molecules. Most substituents showed almost negligible cell penetrating activity, but a cysteine substituent on the 7th valine (SAP(E)‐7C) showed more improved cell penetrating activity than SAP(E). When treated to cells, the negatively‐charged SAP(E)‐7C exhibited much lower degree of co‐localization with acidic endosomes or lysosomes compared to positively‐charged TAT. SAP(E)‐7C could significantly enhance the PTX efficacy on MDA‐MB‐231 cells by non‐covalent complexation with PTX. As a proof‐of‐concept for covalent conjugation of cargo drugs, mercaptoethanol, a model drug, was conjugated to the cysteine residue of SAP(E)‐7C via a disulfide bond, and the glutathione‐dependent release from the conjugate was confirmed. The negatively‐charged SAP(E)‐7C with a cysteine handle can be a useful molecular module for the development of CPP‐based drug delivery carrier.

大多数细胞穿透肽（CPPs）富含带正电荷的氨基酸，但其阳离子性质可能会在实际应用中引发问题。在这项研究中，我们小心地用半胱氨酸取代了SAP（E）序列中的疏水性氨基酸，这是一种罕见的带负电荷的富含脯氨酸的CPP，以增强细胞穿透活性以及货物分子的可逆结合。大多数取代基显示出几乎可以忽略不计的细胞穿透活性，但第7缬氨酸上的半胱氨酸取代基（SAP（E）-7C）显示出比SAP（E）更能提高细胞穿透活性。当对细胞进行处理时，与带正电的TAT相比，带负电的SAP（E）-7C与酸性内涵体或溶酶体的共定位程度要低得多。SAP（E）-7C可通过与PTX的非共价络合显著增强PTX对MDA‐MB‐231细胞的作用。作为货物药物共价偶联的概念证明，巯基乙醇（一种模型药物）通过二硫键与SAP（E）-7C的半胱氨酸残基偶联，并证实了偶联物的谷胱甘肽依赖性释放。带有半胱氨酸手柄的带负电荷的SAP（E）-7C可以成为开发基于CPP的药物递送载体的有用分子模块。

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引用次数: 0

Issue Information 问题信息

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-11-01 DOI: 10.1002/pep2.24300

引用次数: 0

Mutagenesis of cyclotide Cter 27 exemplifies a robust folding strategy for bracelet cyclotides 环核苷酸Cter 27的突变是环核苷酸链折叠策略的一个例子

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-11-01 DOI: 10.1002/pep2.24284

Tien T. Dang, P. Harvey, L. Y. Chan, Yen‐Hua Huang, Q. Kaas, D. Craik

In contrast to Möbius and trypsin inhibitor cyclotides, members of the bracelet subfamily are typically intractable to chemical synthesis and folding. In a significant advance in the field, the bracelet cyclotides ribe 33 and Cter 27 were successfully produced synthetically in moderate yield in a recent study. That synthetic method was a breakthrough as members of the bracelet subfamily of cyclotides had hitherto eluded attempts to be synthetically produced, apart from one report of cyO2 production in which a complicated folding strategy was used. In the current study the successful in vitro folding of three mutants of bracelet cyclotide Cter 27 is reported. This study broadens our understanding of the folding of bracelet cyclotides and elucidates the three dimensional structure of synthetic Cter 27, providing a new class of cyclotide molecular grafting scaffold for drug design applications.

与Möbius和胰蛋白酶抑制剂环肽不同，手镯亚家族的成员通常难以进行化学合成和折叠。在该领域的一个重大进展中，在最近的一项研究中，成功地以中等产量合成了手镯环肽ribe 33和Cter 27。这种合成方法是一个突破，因为除了一份使用复杂折叠策略的cyO2生产报告外，环肽手镯亚家族的成员迄今为止一直未能进行合成生产。在目前的研究中，报道了手镯环肽Cter 27的三个突变体的成功体外折叠。这项研究拓宽了我们对手镯环肽折叠的理解，阐明了合成Cter 27的三维结构，为药物设计应用提供了一类新的环肽分子接枝支架。

引用次数: 2

PL‐101‐WK, a novel tryptophan‐ and lysine‐rich peptide with antimicrobial activity against Staphylococcus aureus PL‐101‐WK，一种新型富含色氨酸和赖氨酸的肽，对金黄色葡萄球菌具有抗菌活性

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-10-05 DOI: 10.1002/pep2.24296

Parvin Zadeh Shahraki, P. Farrokh

Designing short antimicrobial peptides (AMPs), which are active against drug‐resistant bacteria, is a promising way to find new therapeutic agents. In this research, a novel short AMP, PL‐101‐WK, was designed based on PL‐101 (a derivative of plicatamide). Here, the substitution of Phe and His with Trp and Lys was considered. The antimicrobial activity and physicochemical properties of PL‐101‐WK were compared with PL‐101 by in silico analysis. The antimicrobial activity in the presence or absence of NaCl concentration, thermal stability, hemolytic activity, and selectivity of the peptides were determined. By substitution of Lys and Trp residues, positive charge, in vitro stability, and hydrophilicity of PL‐101‐WK were raised compared to the template. PL‐101‐WK had the best minimum inhibitory concentration (MIC) value of 64 μg/ml against Staphylococcus aureus strains, which showed at least 16‐fold reduction when compared to the values of PL‐101. The MICs of PL‐101‐WK were retained toward S. aureus strains at physiological salt concentration. While PL‐101‐WK did not display acceptable thermal stability, it had desirable selectivity against bacteria. The maximum hemolytic activity of PL‐101‐WK was 1.65% at 512 μg/ml. Taken together, increasing positive charge and the presence of Trp residues were enhanced the potential of antibacterial activity of PL‐101.

设计对耐药细菌具有活性的短抗菌肽(AMPs)是寻找新的治疗药物的一种很有前途的方法。在这项研究中，基于PL‐101 (plicatamide的衍生物)设计了一种新的短AMP PL‐101‐WK。这里考虑用Trp和Lys取代Phe和His。通过硅分析比较了PL‐101‐WK与PL‐101的抑菌活性和理化性质。测定了在NaCl浓度存在或不存在情况下的抗菌活性、热稳定性、溶血活性和选择性。通过替换赖氨酸和色氨酸残基，与模板相比，PL‐101‐WK的正电荷、体外稳定性和亲水性都得到了提高。PL‐101‐WK对金黄色葡萄球菌的最低抑菌浓度(MIC)为64 μg/ml，比PL‐101降低了至少16倍。在生理盐浓度下，PL‐101‐WK对金黄色葡萄球菌的mic保持不变。虽然PL‐101‐WK没有表现出可接受的热稳定性，但它对细菌具有理想的选择性。在512 μg/ml浓度下，PL‐101‐WK的最大溶血活性为1.65%。综上所述，正电荷的增加和色氨酸残基的存在增强了PL‐101的抗菌活性。

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引用次数: 0

A Shelf Stable Fmoc Hydrazine Resin for the Synthesis of Peptide Hydrazides. 用于合成肽肼的货架稳定的 Fmoc 肼树脂。

IF 1.5 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-09-01 Epub Date: 2022-04-16 DOI: 10.1002/pep2.24268

Michael J Bird, Philip E Dawson

C-terminal hydrazides are an important class of synthetic peptides with an ever expanding scope of applications, but their widespread application for chemical protein synthesis has been hampered due to the lack of stable resin linkers for synthesis of longer and more challenging peptide hydrazide fragments. We present a practical method for the regeneration, loading, and storage of trityl-chloride resins for the production of hydrazide containing peptides, leveraging 9-fluorenylmethyl carbazate. We show that these resins are extremely stable under several common resin storage conditions. The application of these resins to solid phase peptide synthesis (SPPS) is demonstrated through the synthesis of the 40-mer GLP-1R agonist peptide "P5". These studies support the broad utility of Fmoc-NHNH-Trt resins for SPPS of C-terminal hydrazide peptides.

C 端酰肼是一类重要的合成肽，其应用范围不断扩大，但由于缺乏稳定的树脂连接物来合成更长、更具挑战性的肽酰肼片段，其在化学蛋白质合成中的广泛应用一直受到阻碍。我们介绍了一种利用 9-芴基甲基肼酸盐再生、装载和储存三苯甲基氯树脂以生产含肼多肽的实用方法。我们的研究表明，在几种常见的树脂储存条件下，这些树脂都非常稳定。通过合成 40 聚体 GLP-1R 激动剂肽 "P5"，证明了这些树脂在固相肽合成 (SPPS) 中的应用。这些研究支持 Fmoc-NHNH-Trt 树脂在 C 端肼肽 SPPS 中的广泛应用。

引用次数: 0

Linearized teixobactin is inactive and after sequence enhancement, kills methicillin-resistant Staphylococcus aureus via a different mechanism. 线性化的 teixobactin 没有活性，经过序列增强后，可通过不同的机制杀死耐甲氧西林金黄色葡萄球菌。

IF 1.5 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-09-01 Epub Date: 2022-04-25 DOI: 10.1002/pep2.24269

Qianhui Wu, Biswajit Mishra, Guangshun Wang

Staphylococcus aureus is a highly adaptable pathogen that can rapidly develop resistance to conventional antibiotics such as penicillin. Recently, teixobactin was discovered from uncultivated soil bacteria by using the i-chip technology. This depsipeptide forms an ester bond between the backbone C-terminal isoleucine carboxylic acid and the hydroxyl group of threonine at position 8. Also, it contains multiple nonstandard amino acids, making it costly to synthesize. This study reports new peptides designed by linearizing teixobactin. After linearization and conversion to normal amino acids, teixobactin lost its antibacterial activity. Using this inactive template, a series of peptides were designed via hydrophobic patching and residue replacements. Three out of the five peptides were active. YZ105, only active against Gram-positive bacteria, however, showed the highest cell selectivity index. Different from teixobactin, which inhibits cell wall synthesis, YZ105 targeted the membranes of methicillin-resistant S. aureus (MRSA) based on kinetic killing, membrane permeation, depolarization, and scanning electron microscopy studies. Moreover, YZ105 could kill nafcillin-resistant MRSA, Staphylococcal clinical strains, and disrupted preformed biofilms. Taken together, YZ105, with a simpler sequence, is a promising lead for developing novel anti-MRSA agents.

金黄色葡萄球菌是一种适应性很强的病原体，能迅速对青霉素等传统抗生素产生抗药性。最近，利用 i 芯片技术从未培育的土壤细菌中发现了 teixobactin。这种去肽在骨架 C 端异亮氨酸羧酸和第 8 位苏氨酸的羟基之间形成一个酯键。此外，它还含有多个非标准氨基酸，因此合成成本较高。本研究报告了通过线性化 Teixobactin 设计的新肽。在线性化并转化为正常氨基酸后，teixobactin 失去了抗菌活性。利用这种非活性模板，通过疏水修补和残基替换设计出了一系列肽。五种肽中有三种具有活性。YZ105 只对革兰氏阳性菌有活性，但却显示出最高的细胞选择性指数。与抑制细胞壁合成的teixobactin不同，根据动力学杀灭、膜渗透、去极化和扫描电子显微镜研究，YZ105靶向耐甲氧西林金黄色葡萄球菌（MRSA）的膜。此外，YZ105 还能杀灭耐纳西林的 MRSA 和葡萄球菌临床菌株，并破坏已形成的生物膜。综上所述，YZ105 的序列更简单，是开发新型抗 MRSA 药物的一个很有前景的先导物。

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引用次数: 0

Structured cyclic peptide mimics by chemical ligation 化学连接的结构环肽模拟物

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-09-01 DOI: 10.1002/pep2.24266

B. C. Atkinson, A. Thomson

We report the development of a β‐turn mimic that allows the direct formation of cyclic peptides through a spontaneous cyclisation under standard solid phase peptide synthesis (SPPS) cleavage conditions. The mimic is formed via an acylhydrazone, which is either reduced in situ by triisopropylsilane‐trifluoroacetic acid, or which can be isolated and reduced in a separate step. This method uses commercially available reagents and is compatible with manual and automated SPPS methods. The cyclisation is tolerant of polar residues at the C‐terminal position, with the exception of asparagine, for which a subsequent structural rearrangement similar to aspartimide formation was observed. The cyclisation method has been shown to tolerate ring sizes equivalent to 5–10 amino acid residues. We have used this method to design and synthesise potential selective integrin binding sequences with controlled conformations.

我们报道了一种β - turn模拟物的开发，该模拟物允许在标准固相肽合成(SPPS)裂解条件下通过自发环化直接形成环状肽。模拟物是通过酰基腙形成的，它可以被三异丙基硅烷-三氟乙酸原位还原，或者可以在单独的步骤中分离和还原。该方法使用市售试剂，可与手动和自动SPPS方法兼容。环化对C末端的极性残基是耐受的，但天冬酰胺除外，其随后的结构重排类似于阿斯巴胺的形成。环化方法已被证明可以容忍相当于5-10个氨基酸残基的环大小。我们已经使用这种方法来设计和合成具有控制构象的潜在选择性整合素结合序列。

引用次数: 0

Synoeca‐MP: New insights into its mechanism of action by using NMR and molecular dynamics simulations approach Synoeca‐MP：利用NMR和分子动力学模拟方法对其作用机制的新见解

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-07-30 DOI: 10.1002/pep2.24293

E. Alves, Bruno de Paula Oliveira de Santos, L. Rodrigues, Carlos Daniel Pereira Freitas, Lucianna Helene Silva dos Santos, S. C. Dias, O. Franco, L. Lião, M. D. de Magalhães

Synoeca‐MP is a 14‐residue amidated peptide, belongs to the mastoparan family and it is found in the venom of the wasp Synoeca surinama and has antibacterial and antifungal activity. The low cytotoxicity of the peptide also makes it an excellent candidate for drug development. To better understand its selectivity and interaction with the membrane, the peptide behavior in membrane‐like environments was studied here and the peptide structure in SDS micelles was determined by NMR spectroscopy. The behavior of the peptide in hydrophobic media and in different pH ranges was studied by CD spectroscopy. The incorporation of residues into the anionic micelles was studied by hydrogen‐deuterium exchange. The peptide stability and insertion in the micelles was studied by molecular dynamics simulations. Synoeca‐MP, bound to SDS micelles, exhibits a partial α‐helix conformation, with the first five residues and the last two unfolded. H/D exchange showed that the peptide has a slow exchange rate. After 164 h, four residues had not yet completed H/D substitution, suggesting parallel alignment of the peptide with the micelle, mainly due to the hydrophobic interface. This may indicate a carpet interaction model of the peptide with micelles. The molecular simulation study of peptide showed that the peptide consists of a well‐folded alpha‐helix core and unfolded extremities, which are responsible for the nature of the peptide interaction. The biophysical analyses can improve the atomic understanding of the mode of action of the peptide and help in future improvements of the peptide for clinical usage.

Synoeca‐MP是一种14个残基的酰胺化肽，属于乳突蛋白酶家族，存在于胡蜂鱼糜的毒液中，具有抗菌和抗真菌活性。该肽的低细胞毒性也使其成为药物开发的优秀候选者。为了更好地了解其选择性和与膜的相互作用，本文研究了肽在类膜环境中的行为，并通过NMR光谱测定了肽在SDS胶束中的结构。通过CD光谱研究了肽在疏水介质和不同pH范围内的行为。通过氢-氘交换研究了残留物在阴离子胶束中的结合。通过分子动力学模拟研究了肽在胶束中的稳定性和插入性。Synoeca‐MP与SDS胶束结合，呈现部分α螺旋构象，前五个残基和后两个未折叠。H/D交换表明该肽具有缓慢的交换速率。164之后 h、四个残基尚未完成h/D取代，这表明肽与胶束平行排列，主要是由于疏水界面。这可能表明肽与胶束的地毯式相互作用模型。肽的分子模拟研究表明，肽由折叠良好的α-螺旋核心和未折叠的末端组成，这是肽相互作用的本质。生物物理分析可以提高对肽作用模式的原子理解，并有助于未来临床使用肽的改进。

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引用次数: 0

Advances in the use of plants as potential biofactories in the production of antimicrobial peptides 利用植物作为潜在生物工厂生产抗菌肽的研究进展

IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-07-06 DOI: 10.1002/pep2.24290

Cristiane dos Santos, O. Franco

Plants subjected to phytopathogens can synthesize peptides with antimicrobial properties. In the last few decades, there has been an impressive increase in the prospection of antimicrobial peptides (AMPs) due to continuous demand for the development and manufacture of new antibiotics. In this setting, plants have attracted scientific and pharmaceutical interest and are considered promising AMPs biofactories. However, it is a great challenge to explore the diversity of actions needed to obtain a pharmaceutical product with AMPs derived from plants on a large scale. This review presents the last 5 years main findings on plants used as AMPs biofactories. Published works in this period were reviewed, and perspectives are presented on recombinant AMPs for drug production that appear in a plant‐based system, as well as products available on the market.

受到植物病原体感染的植物可以合成具有抗菌特性的肽。在过去的几十年里，由于对新抗生素的开发和制造的持续需求，抗菌肽（AMP）的前景有了令人印象深刻的增长。在这种背景下，植物吸引了科学和制药界的兴趣，被认为是有前途的AMPs生物因子。然而，探索大规模获得具有源自植物的AMP的药物产品所需的作用的多样性是一个巨大的挑战。本综述介绍了最后5个多年来关于用作AMPs生物因子的植物的主要发现。回顾了这一时期发表的工作，并对出现在植物系统中的用于药物生产的重组AMP以及市场上可用的产品提出了展望。

引用次数: 3

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IF 2.4 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptide Science

Pub Date : 2022-07-01 DOI: 10.1002/pep2.24292

引用次数: 0

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