SYNAPTA: An artificial genetic system and its application for the generation of novel nucleic acid therapeutics

SYNAPTA：人工遗传系统及其在产生新型核酸疗法中的应用

• 批准号: BB/I004793/1
• 负责人: Philipp Holliger
• 金额: $ 35.04万
• 依托单位: MRC Centre Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004793%2F1
• 关键词: SYNAPTA; artificial; genetic; system; its

Life's diversity is largely based on the versatility of two polymers: polyeptides (i.e. proteins) and polynucleotides (nucleic acids). Nucleic acids in particular display unique properties beyond their ability to encode genetic information, which make them important tools in chemistry, biotechnology, nanotechnology and medicine. Nucleic acids also have enormous potential as therapeutics but suffer from systemic constraints inherent in DNA and RNA chemistry such as poor serum / nuclease stability. Aptamers are a promising class of biomolecular therapeutics based on structured single-stranded nucleic acids with the potential to rival antibodies in some clinical settings. A broad spectrum of both RNA- and DNA-based aptamers have been described directed against a wide-range of targets and several are currently undergoing in clinical trails underlining their potential. However, reagents based on natural nucleic acids such as RNA or DNA are not optimal with respect to a number of desirable properties for clinical reagents and therapeutics, notably in vivo stability and bioavailability. In principle, aptamers may be stabilized (post-selection) by medicinal chemistry approaches and this approach has been validated by the Macugen, the 1st aptamers based drug, which has been approved for the treatment of macular degeneration. However, post-selection modifications can alter and / or weaken aptamer structure and target interactions and may modify aptamer specificity. Therefore direct selections using modified nucleic acid chemistries would be desirable. Many novel nucleic acid structures have been built with a view towards increased orthogonality. The challenge here is to design scaffolds that lead to minimal interaction / interference with the cellular genetic machinery while simultaneously maintaining an ability to communicate with it. A different approach towards chemically orthogonal nucleic acids involves the modification of the backbone but leaves the informational nucleobases intact. Replacement of the canonical ribofuranose with other pentoses (or hexoses and tetroses) can indeed have dramatic effects on helical conformation and duplex stability and formation. We have selected two unnatural nucleic acid architectures, Hexitol nucleic acid (HNA) and Cyclohexenyl nucleic acids (CeNA) as our backbone structures. Both HNA and CeNA are completely resistant to nuclease degradation and appear not to be substrates for DNA or RNA modifying enzymes. Significantly, they are non-toxic to cells as nucleotides and therefore appear to be not recognized as substrates by the cellular replication, transcription and translation machine. This proposal aims to develop the platform technologies needed to deliver tailor-made 'designer' ligands of high serum stability, defined compact structure and expanded functionality based on these novel chemistries with obvious potential as a novel class of bio-therapeutics. These novel polymers will also provide insights into the parameters of molecular information storage and propagation through the study of artificial genetic systems entirely based on unnatural chemistry.

生命的多样性在很大程度上是基于两种聚合物的多样性：多肽(即蛋白质)和多核苷酸(核酸)。特别是核酸表现出的独特性质超出了它们编码遗传信息的能力，这使它们成为化学、生物技术、纳米技术和医学的重要工具。核酸也具有巨大的治疗潜力，但受到DNA和RNA化学固有的系统性限制，如血清/核酸酶稳定性差。适配子是一类很有前途的生物分子疗法，基于结构单链核酸，在一些临床环境中有可能与抗体竞争。已经描述了针对广泛靶点的基于RNA和DNA的广泛适体，其中几个目前正在进行临床试验，突显了它们的潜力。然而，基于天然核酸的试剂，如RNA或DNA，在临床试剂和治疗的许多理想性质方面并不是最理想的，特别是在体内的稳定性和生物利用度。原则上，适配子可以通过药物化学方法稳定(选择后)，这种方法已经被Macugen验证，这是第一个基于适配子的药物，已被批准用于治疗黄斑变性。然而，选择后的修饰可以改变和/或削弱适配子结构和靶相互作用，并可能改变适配子的特异性。因此，使用改进的核酸化学进行直接选择将是可取的。为了提高正交性，已经建立了许多新的核酸结构。这里的挑战是设计支架，使其与细胞遗传机制的相互作用/干扰降至最低，同时保持与其沟通的能力。另一种不同的方法是获得化学上正交的核酸，包括对骨架的修饰，但保持信息碱基不变。用其他戊糖(或己糖和四聚糖)取代典型的呋喃核糖确实会对螺旋构象和双链稳定性和形成产生显著影响。我们选择了两个非天然的核酸结构，己醇核酸(HNA)和环己烯基核酸(CENA)作为我们的主干结构。海航和CENA都完全抵抗核酸酶降解，似乎不是DNA或RNA修饰酶的底物。值得注意的是，它们作为核苷酸对细胞无毒，因此似乎不被细胞复制、转录和翻译机器识别为底物。这项提议旨在开发所需的平台技术，以提供定制的“设计”配体的高血清稳定性，明确的紧凑结构和扩展的功能，基于这些新的化学物质，具有明显的潜力作为一种新型的生物治疗药物。这些新型聚合物还将通过完全基于非天然化学的人工遗传系统的研究，提供对分子信息存储和传播参数的见解。

项目成果

Towards applications of synthetic genetic polymers in diagnosis and therapy.

• DOI: 10.1016/j.cbpa.2014.09.022
• 发表时间: 2014-10
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Alexander I. Taylor;Sebastian Arangundy-Franklin;P. Holliger

Protein Engineering Handbook: Volume 3

蛋白质工程手册：第 3 卷

• 发表时间: 2012
• 作者: Pinheiro, V.B.

Synthetic genetic polymers capable of heredity and evolution.

• DOI: 10.1126/science.1217622
• 发表时间: 2012-04-20
• 期刊: Science (New York, N.Y.)
• 作者: Pinheiro VB;Taylor AI;Cozens C;Abramov M;Renders M;Zhang S;Chaput JC;Wengel J;Peak-Chew SY;McLaughlin SH;Herdewijn P;Holliger P
• 通讯作者: Holliger P