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Emerging peptide science in the United Kingdom
Peptide Science ( IF 2.4 ) Pub Date : 2021-01-25 , DOI: 10.1002/pep2.24216
Andrew G. Jamieson 1
Affiliation  

It is with great pleasure that I present this special issue of Peptide Science focused on the state‐of‐the‐art in peptide research from laboratories in the UK. This issue is the fifth of an international series of special issues that highlights Emerging Peptide Science research from countries with an active community of scientists working in the field. The previous issues have covered recent scientific advances from colleagues in Australia, Canada, Italy and Japan. Here four Reviews and seven research articles describe some of the exceptional science currently being carried out by UK‐based peptide scientists.

There is a strong peptide science community in the UK. This is evidenced in part by the busy annual conference schedule, and the activities of both the Peptide and Protein Science Group (PPSG), and Chemical Biology and Bio‐organic Chemistry Group (CBBG) of the Royal Society of Chemistry (RSC). Core meetings in the UK calendar include the annual British Peptide Society/PPSG Chemistry and Biology of Peptides Symposium and the Peptides Congress (organised by Oxford Global).

Excellence in peptide science is recognised in the UK through the biennial RSC Medimmune Protein and Peptide Science Award. One of our contributors, Professor Ali Tavassoli (University of Southampton) was the award winner in 2017 for his exceptional work on genetically encoded cyclic peptide libraries and their application in the discovery of protein‐protein interaction inhibitors.

Importantly, the UK community has created and supports a vibrant network for early career researchers in the peptide sciences through the annual PPSG Early Stage Researcher Meeting and CBBG Postgraduate Symposium. I would like to take this opportunity to congratulate the early career researchers who have been involved in delivering the science reported in this issue. You are the lifeblood and future of peptide science and I speak for all the principal investigators in thanking you for your efforts in this regard. It is of note that two of the contributions are dedicated to colleagues and mentors who have inspired these researchers. Dr Craig Jamieson (Strathclyde University) provides a dedication to Professor Robert Ramage FRS, and Professor Marc Vendrell (University of Edinburgh) dedicates his team's Review to Professor Nick Read. It is easy for most people reading this editorial to get excited about peptide science, however to excite and enthuse the next generation of peptide scientists is arguably one of the most important contributions one can make to the field.

The special issue begins with four Reviews on new transformative peptide technologies. The first two articles focus on applications of cyclic peptides. The Review from Professor Marc Vendrell at the University of Edinburgh covers the development and application of fluorescent cyclic peptides. The multitude of synthesis strategies, methods of characterisation and validation of these imaging agents in biological studies is reviewed. Next, is a review of cyclic peptides discovered through display technologies by Professor Akane Kawamura at Newcastle University. A strong focus is placed on the importance of peptide secondary structure for bioactivity and the work highlights structure‐based design as an extremely useful strategy to obtain improved activity and physicochemical properties. The subsequent Review by Professor John Howl from the University of Wolverhampton covers the emerging area of bioportides, a bi‐functional sub‐class of cell penetrating peptides that also act as regulators of protein‐protein interactions. The final Review in the series, by Professor Alison Hulme from the University of Edinburgh, provides a critical analysis of stapled peptide design methods. Particular attention is paid to lessons that can be learned from the available crystal structures of stapled peptides bound to their target proteins. The article also includes an excellent overview of methods to improve pharmacokinetic properties of stapled peptides that target a broad range of therapeutically relevant protein‐protein interactions.

Next in this special issue, seven original research articles highlight some of the work being done in laboratories across the UK at present. The initial two articles focus on the development of antimicrobials.

The first is by the group of Professor Mark Bradley at the University of Edinburgh. Fluorescently tagged antimicrobial peptides were produced and shown to effectively label both fungal and bacterial species (Gram positive and negative) using fluorescent confocal microscopy. These peptides thus have potential applications for the cost‐effective and rapid diagnosis of infection. Insight into the mechanism of binding was obtained through disruption of the helical structure of the peptides using mixed L/D‐analogues, suggesting the Shai‐Matsuzaki‐Huang model of membrane interaction. The following article is by Dr Gary Laverty from Queen's University Belfast. A library of linear lipopeptides inspired by the polymyxins were synthesised and the in vitro antibacterial and antibiofilm activity assessed. Two of these analogues were active against both Gram‐positive and Gram‐negative bacteria. Next, Professor Ali Tavassoli from the University of Southampton reports the development of a new screening platform based on a bacterial three‐hybrid system that detects peptide ligand induced protein association. The platform was validated using rapamycin mediated mTOR‐FKBP12 dimerisation. Protein association leads to the expression of life/death reporter genes and a fluorescent readout.

The subsequent four articles describe the application of stapled peptides to different targets and the development of new stapled peptide chemistries. In the first, my own research group at the University of Glasgow report the development of stapled peptide analogues of the μ‐conotoxin KIIIA and their activity against human voltage‐gated sodium channels hNaV1.4 and hNaV1.6. Seven different types of helix conformational constraint were applied and two of the analogues were biologically active. Conformational analysis using NMR spectroscopy provided insight to the structural requirements for bioactivity of this important class of disulphide‐rich peptide. The next work, from Dr Craig Jamieson at the University of Strathclyde, reports the development of stapled peptide mimics of the ubiquitin conjugating enzyme, E2‐25K, and their assessment as antagonists of the protein‐protein interaction between E2‐25K and the Alzheimer's Disease‐associated ubiquitin mutant Ubb + 1. Four analogues were shown to reduce incorporation of Ubb + 1 into polyubiquitin chains as a result of selective inhibition of the interaction between E2‐25K and Ubb + 1. Dr Chris Coxon at Heriot‐Watt University then reports the application of two‐level factorial design to the reaction conditions of a hexafluorobenzene two‐component peptide stapling reaction. Reactivity and product selectivity are initially investigated using hexafluorobenzene and N‐acetyl cysteine, and an elegant 19F NMR characterisation method developed. Optimised reaction conditions were then applied to a model peptide which rapidly cyclised to provide the product with excellent crude purity. A solid‐phase version of the reaction was also developed and validated by cyclisation of a Skin Penetrating and Cell Entering disulphide peptide. The special issue concludes with an excellent article from Professor Andrew Wilson at the University of Leeds. Structural optimisation of a new reversible maleimide‐based helix constraint is reported, whereby a series of model pentapeptide analogues incorporating Cys or hCys at the i, i + 4 positions were synthesised. Conformational analysis using circular dichroism and NMR spectroscopy revealed the most effective constraint to induce helicity.

I would like to thank all of the authors for contributing to this special UK issue of Peptide Science. These primary research articles and Reviews provide a snapshot of the excellent peptide science ongoing in the UK, I hope you enjoy reading them!



中文翻译:

英国的新兴肽科学

我非常高兴地介绍本期《肽科学》特刊,重点介绍了来自英国实验室的最新肽研究。本期是国际专题系列文章的第五期,该系列着重介绍了来自活跃于该领域的科学家活跃国家的国家的新兴肽科学研究。先前的问题涵盖了澳大利亚,加拿大,意大利和日本的同事最近的科学进展。这里有四篇评论和七篇研究文章描述了英国肽科学家目前正在开展的一些特殊科学。

英国有一个强大的肽科学界。繁忙的年度会议时间表以及肽和蛋白质科学小组(PPSG)以及皇家化学学会(RSC)的化学生物学和生物有机化学小组(CBBG)的活动都部分证明了这一点。英国日历中的核心会议包括年度英国肽学会/ PPSG肽化学和生物学研讨会和肽会议(由牛津全球组织)。

两年一度的RSC Medimmune蛋白质和肽科学奖在英国认可了肽科学方面的卓越成就。我们的贡献者之一,南安普顿大学的Ali Tavassoli教授在2017年因其在遗传编码的环肽文库及其在发现蛋白-蛋白相互作用抑制剂中的应用方面的杰出工作而获奖。

重要的是,英国社会通过每年的PPSG早期研究员会议和CBBG研究生座谈会,为肽科学的早期职业研究人员创建并支持了一个充满活力的网络。我想借此机会祝贺参与本期报道的科学工作的早期职业研究人员。您是肽科学的生命线和未来,我感谢所有主要研究人员感谢您在这方面的努力。值得一提的是,其中有两份献给那些启发了这些研究人员的同事和导师。Craig Jamieson博士(斯特拉克莱德大学)为Robert Ramage FRS教授献身,而Marc Vendrell教授(爱丁堡大学)为Nick Read教授献计献策。

特刊开始于对新型转化肽技术的四篇评论。前两篇文章重点介绍环肽的应用。爱丁堡大学的马克·文德雷尔教授的评论涵盖了荧光环状肽的开发和应用。综述了生物学研究中这些成像剂的多种合成策略,表征方法和验证方法。接下来,回顾一下纽卡斯尔大学的川村茜(Akane Kawamura)教授通过展示技术发现的环肽。肽二级结构对生物活性的重要性非常受关注,这项工作强调了基于结构的设计是获得改善的活性和理化性质的极为有用的策略。伍尔弗汉普顿大学的John Howl教授随后发表的《综述》涵盖了生物部分的新兴领域,这是一种细胞穿透肽的双功能亚类,也可作为蛋白质与蛋白质相互作用的调节剂。爱丁堡大学的Alison Hulme教授对该系列的最后一篇综述进行了对短肽设计方法的批判性分析。特别注意的是可以从与目标蛋白结合的固定肽的可用晶体结构中吸取的教训。这篇文章还对改善钉合肽的药代动力学特性的方法进行了很好的概述,这些钉合肽针对广泛的治疗相关蛋白-蛋白相互作用。细胞穿透肽的双功能亚类,也可作为蛋白质与蛋白质相互作用的调节剂。爱丁堡大学的Alison Hulme教授对该系列的最后一篇综述进行了对短肽设计方法的批判性分析。特别注意的是可以从与目标蛋白结合的固定肽的可用晶体结构中学到的课程。这篇文章还对改善钉合肽的药代动力学特性的方法进行了很好的概述,这些钉合肽针对广泛的治疗相关蛋白-蛋白相互作用。细胞穿透肽的双功能亚类,也可作为蛋白质与蛋白质相互作用的调节剂。爱丁堡大学的Alison Hulme教授对该系列的最后一篇综述进行了对短肽设计方法的批判性分析。特别注意的是可以从与目标蛋白结合的固定肽的可用晶体结构中吸取的教训。这篇文章还对改善钉合肽的药代动力学特性的方法进行了很好的概述,这些钉合肽针对广泛的治疗相关蛋白-蛋白相互作用。特别注意的是可以从与目标蛋白结合的固定肽的可用晶体结构中吸取的教训。这篇文章还对改善钉合肽的药代动力学特性的方法进行了很好的概述,这些钉合肽针对广泛的治疗相关蛋白-蛋白相互作用。特别注意的是可以从与目标蛋白结合的固定肽的可用晶体结构中吸取的教训。这篇文章还对改善钉合肽的药代动力学特性的方法进行了很好的概述,这些钉合肽针对广泛的治疗相关蛋白-蛋白相互作用。

在本期特刊中,接下来的七篇原创研究文章重点介绍了目前在英国实验室中正在进行的一些工作。最初的两篇文章侧重于抗菌剂的开发。

第一个是爱丁堡大学的Mark Bradley教授小组的研究。产生荧光标记的抗菌肽,并显示可使用荧光共聚焦显微镜有效标记真菌和细菌物种(革兰氏阳性和阴性)。因此,这些肽具有潜在的应用价值,可以快速,经济地诊断感染。通过使用混合的L / D-类似物破坏肽的螺旋结构,可以深入了解结合机理,这表明了Shai-Matsuzaki-Huang膜相互作用模型。以下文章是贝尔法斯特女王大学的Gary Laverty博士撰写的。合成了由多粘菌素激发的线性脂肽文库,并在体外评估抗菌和生物膜活性。这些类似物中的两个对革兰氏阳性和革兰氏阴性细菌均具有活性。接下来,来自南安普敦大学的Ali Tavassoli教授报告了基于细菌三杂交系统的新筛选平台的开发,该系统可检测肽配体诱导的蛋白质缔合。该平台已使用雷帕霉素介导的mTOR-FKBP12二聚体进行了验证。蛋白质缔合导致生命/死亡报告基因的表达和荧光读数。

随后的四篇文章介绍了将钉书钉肽应用于不同的靶标以及新的钉书钉肽化学的发展。首先,我自己在格拉斯哥大学的研究小组报告了μ-芋螺毒素KIIIA的短肽类似物的开发及其对人电压门控钠通道hNa V 1.4和hNa V的活性1.6。应用了七种不同类型的螺旋构象约束,其中两个类似物具有生物活性。使用NMR光谱进行构象分析可以深入了解这一重要的富含二硫键的肽类对生物活性的结构要求。斯特拉斯克莱德大学的Craig Jamieson博士的下一份工作报告了泛素结合酶E2-25K的钉合肽模拟物的发展以及它们作为E2-25K与阿尔茨海默氏病之间蛋白质相互作用的拮抗剂的评估相关的泛素突变体Ubb +1。由于选择性抑制E2-25K和Ubb + 1的相互作用,显示出四个类似物可减少Ubb + 1掺入多泛素链。Heriot-Watt大学的Chris Coxon博士随后报告了二级因子设计在六氟苯二组分肽吻合反应的反应条件中的应用。最初使用六氟苯和开发了N乙酰半胱氨酸和一种优雅的19 F NMR表征方法。然后将优化的反应条件应用于模型肽,该模型肽快速环化以提供具有优异的粗制纯度的产物。还开发了反应的固相形式,并通过皮肤渗透和细胞进入二硫化物肽的环化作用进行了验证。特刊以利兹大学安德鲁·威尔逊教授的精彩文章作为结尾。据报道,新的可逆基于马来酰亚胺的螺旋约束条件进行了结构优化,从而在ii处结合了Cys或hCys的一系列五肽类似物模型 合成了4个位置。使用圆二色性和NMR光谱进行的构象分析显示出最有效的限制因素来诱导螺旋。

我要感谢所有作者为英国《肽科学》这一特别刊物所作的贡献。这些主要的研究文章和评论概述了英国正在进行的优秀肽科学,希望您喜欢阅读它们!

更新日期:2021-01-26
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