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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/M001873/1
负责人：
Jody Mason
金额：
$ 3.37万
依托单位：
University of Essex
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FM001873%2F1
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-蛋白质相互作用介导大多数生物学过程，因此是重要的治疗靶点。蛋白质的生物活性通常仅源于其表面上的一个小的局部区域。在分子水平上，这些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-折叠。创造能够模拟这些区域同时保留其结构的分子是药物设计的有吸引力的选择。然而，蛋白质的短区域通常不能在蛋白质的其余部分不存在的情况下采用这些结构。相反，它们占据随机结构，除了其他缺点之外，这些结构容易降解，例如它们不能穿过生物膜和生物利用度差。为了解决这些问题，我们将与二级结构模拟物的世界领导者费尔利合作，创造能够单独形成生物活性α-螺旋和β-折叠的肽。这将通过将螺旋或链诱导系链引入我们不断增长的文库衍生肽集合中来实现。较短的受约束肽可以衍生自已知以高亲和力结合其靶标的较大肽。我们的工作将集中在两个关键领域，我们有跟踪记录：i）创造肽拮抗致癌转录调节因子，激活蛋白-1。我们先前已经使用文库筛选测定来衍生一系列能够拮抗功能的肽。我们已经与费尔利合作，通过靶向一个称为cFos的AP-1伴侣并在此过程中脱落超过40%的肽来证明这种方法的可行性。使用这种方法，我们能够衍生出对其靶蛋白具有特异性的稳定的螺旋约束肽，其也抵抗降解（Rao等人，PLOS One 2013）。我们相信，可以通过靶向另一种AP-1组分（称为cJun）来实现更高的亲和力相互作用，其中可以形成高结合亲和力所需的更多疏水相互作用。先前的相关工作已经证明，这种方法可以产生短至五个氨基酸的栓系肽（Harrison等人，PNAS，2010），其能够满足药物所必需的许多要求，例如高稳定性和对生物分解的抗性。ii）产生能够调节淀粉样蛋白形成的肽。我们已经使用文库筛选来衍生与阿尔茨海默氏β-淀粉样肽结合的小β-链肽（阿塞拉等人，Protein Eng Des Sel 2013）。我们现在寻求与费尔利合作，创造这些短肽的模拟物，从而改进能够规避上述许多问题的化合物。为了实现这些目标，梅森将前往分子生物科学研究所（IMB）在昆士兰大学的三次访问超过三年，以进一步发展我们与费尔利集团的合作。费尔利是国际知名的研究和意见领袖在化学，生物化学，药理学和药物发现。该奖项将允许梅森获得新的技能和技术，可以带回埃塞克斯和进一步发展，在英国，除了交流思想和进一步发展的合作。已经开发了用于稳定α-螺旋和β-链的方法，通常将有相当大的范围将这些技术以及肽和肽模拟物设计的后续规则应用于其他肽系统。最后，在昆士兰州，也将有足够的机会举办研讨会，并会见和讨论与IMB的其他成员（如教授格伦国王和大卫克雷克）谁在开发肽为基础的药物有类似的兴趣研究计划。