Establishing an Approach for the Selection and Design of Secondary Structure Mimetics to Antagonise Protein-protein Interactions.

建立一种选择和设计二级结构模拟物以拮抗蛋白质-蛋白质相互作用的方法。

基本信息

批准号：
EP/M001873/2
负责人：
Jody Mason
金额：
$ 3.37万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FM001873%2F2
关键词：
Establishing Approach Selection Design Secondary

项目摘要

Protein-protein interactions mediate most biological processes and are therefore important therapeutic targets. The biological activity of a protein usually stems from only a small localised region on its surface. At the molecular level such regions often correspond to key secondary structures known as alpha-helices or beta-sheets that reside within the protein. Creating molecules able to mimic these regions while retaining their structure are attractive options for drug design. However short regions of a protein are usually unable to adopt these structures in the absence of the rest of the protein. Rather, they populate random structures that are susceptible to degradation in addition to other shortcomings such as their inability to cross biological membranes and poor bioavailability. To circumvent these issues we will collaborate with the Fairlie, a world leader in secondary structure mimetics, to create peptides that are able to form bioactive alpha-helices and beta-sheets in isolation. This will be achieved by introducing helix- or strand-inducing tethers into our growing collection of library derived peptides. Shorter constrained peptides can be derived from larger peptides known to bind with high affinity to their target. Our efforts will focus on two key areas in which we have track record:i) creating peptides to antagonise the oncogenic transcriptional regulator, Activator Protein-1. We have previously used library screening assays to derive a range of peptides capable of antagonising function. We have already worked with Fairlie to demonstrate feasibility for this approach by targeting one AP-1 partner known as cFos and shedding over 40% of the peptide in the process. Using this approach we were able to derive stable helix-constrained peptides specific for their target protein that also resisted degradation (Rao et al, PLOS One 2013). We believe that much high affinity interactions can be achieved by targeting another AP-1 component, known as cJun, where many more hydrophobic interactions required for high binding affinity can be formed. Previous related work has demonstrated that this approach can yield tethered peptides as short as five amino acids (Harrison et al, PNAS, 2010) that are able to meet many of the requirements necessary for a drug, such as high stability and resistance to biological breakdown. ii) Creating peptides capable of modulating amyloid formation. We have used library screening to derive small beta-strand peptides that bind to the Alzheimer's beta-amyloid peptide (Acerra et al, Protein Eng Des Sel 2013). We now seek to collaborate with Fairlie in creating mimetics of these short peptides that result in improved compounds that are able to circumvent many of the above issues. To achieve these goals Mason will travel to the Institute for Molecule Bioscience (IMB) at the University of Queenland on three visits over three years to further develop our collaboration with the Fairlie group. Fairlie is internationally known as a research and opinion leader in chemistry, biochemistry, pharmacology, and drug discovery. The award will permit Mason to gain new skills and techniques that can be brought back to Essex and further developed in the UK, in addition to the exchange of ideas and the further development of the collaboration. Having developed methods for stabilising alpha-helices and beta-strands in general there will be considerable scope to apply these techniques, and consequent rules for peptide and peptide mimetic design, to other peptide systems. Finally while at Queensland there will also be ample opportunity to hold seminars and meet and discuss research plans with other members of the IMB (e.g. Professors Glenn King and David Craik) who have similar interests in developing peptide-based drugs.

蛋白质蛋白相互作用介导了大多数生物学过程，因此是重要的治疗靶标。蛋白质的生物学活性通常源自其表面上的一个小局部区域。在分子水平上，这种区域通常对应于蛋白质内的关键二级结构，称为α-螺旋或β片。创建能够模仿这些区域的分子，同时保留它们的结构是药物设计的有吸引力的选择。但是，在没有其余蛋白质的情况下，蛋白质的短区域通常无法采用这些结构。相反，除了其他缺点（例如无法跨越生物膜和差的生物利用度）之外，它们填充了容易降解的随机结构。为了解决这些问题，我们将与Fairlie合作，Fairlie是二级结构的世界领导者，以创建能够隔离地形成生物活性α-螺旋和β片的肽。这将通过将螺旋 - 诱导螺旋的系tethers引入我们越来越多的图书馆衍生肽集合中来实现。较短的约束肽可以源自已知与其靶标有高亲和力结合的较大肽。我们的努力将重点放在我们具有记录记录的两个关键领域：i）创建肽来对抗致癌转录器，即激活蛋白-1。我们以前已经使用了库筛选测定法来得出一系列能够拮抗功能的肽。我们已经与Fairlie合作，通过针对一个称为CFO的AP-1合作伙伴并在此过程中删除40％以上的肽，以证明这种方法的可行性。使用这种方法，我们能够得出针对其靶蛋白的稳定螺旋构约束的肽，该肽也抵抗了降解（Rao等，PLOS One 2013）。我们认为，可以通过靶向另一个称为CJUN的AP-1分量来实现许多高亲和力的相互作用，在该分量中，可以形成高结合亲和力所需的更多疏水相互作用。以前的相关工作表明，这种方法可以产生短暂的蛋白质肽，以至于五个氨基酸（Harrison等，PNAS，2010年）能够满足药物所需的许多要求，例如高稳定性和对生物分解的耐药性。 ii）创建能够调节淀粉样蛋白形成的肽。我们已经使用了库筛选来得出与阿尔茨海默氏蛋白β-淀粉样蛋白肽结合的小β链肽（Acerra等，蛋白质Eng des SEL 2013）。现在，我们寻求与Fairlie合作，以创建这些短肽的模仿，从而改善了能够避免上述许多问题的化合物。为了实现这些目标，梅森将在三年内进行三次访问，前往皇后区分子生物科学研究所（IMB），进一步发展我们与Fairlie Group的合作。 Fairlie在国际上被称为化学，生物化学，药理学和药物发现的研究和意见领导者。该奖项将使梅森能够获得新的技能和技术，除了交流思想和协作的进一步发展外，还可以带回埃塞克斯并进一步发展。一般而言，在开发了稳定α-螺旋和β链的方法之后，将有相当大的范围应用这些技术，以及随之而来的肽和肽模拟设计的规则，将其用于其他肽系统。最终，在昆士兰州，还将有足够的机会与IMB的其他成员（例如Glenn King和David Craik教授）举行研讨会并与研究计划进行会议和讨论，他们对开发基于肽的药物有相似的兴趣。