Enzymatic methods for assembly of nucleic acid therapeutic agents

用于组装核酸治疗剂的酶促方法

• 批准号: 2777796
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2777796
• 关键词: Enzymatic; methods; assembly; nucleic; acid

CONFIDENTIALModified nucleic acids have emerged as a powerful new class of therapeutic agents for the prevention and treatment of a range of diseases (e.g. Inclisiran, a revolutionary cholesterol lowering drug. Over 150 clinical trials are also ongoing using the main types of nucleic acid drugs, antisense oligonucleotides (ASOs) or small interfering RNAs (siRNA), for cancer, cardiovascular, neurodegenerative and infectious diseases etc. ASOs are short single stranded nucleic acids (oligonucleotides) that hybridise with messenger RNA (mRNA), modulating gene expression by blocking progression of the ribosome or inducing cleavage of the mRNA through recruitment of a ribonuclease enzyme (RNaseH). siRNA are short double stranded RNA molecules that bind to specific proteins in the cell to form a complex (RISC) which can cleave complementary mRNA targets. Despite their massive potential the production of these 'magic bullets' is extremely challenging, as extensive modification is required to evade nuclease degradation and to improve affinity for the mRNA target. In addition, their cellular uptake can be problematic, which often requires conjugation with other molecules to aid delivery. Currently solid phase synthesis is used to assemble ASOs and siRNAs. However, this requires an excess of costly precursors (monomers), toxic reagents, deleterious solvents and is very difficult to scale up, making treatments expensive and preventing development of new drugs. In this project we will develop more sustainable and scalable enzymatic methods (industrial biotechnology) to deliver essential ASO and siRNA medicines under mild conditions, in water, utilising more benign enzymes and renewable precursors. (see application form for further details).

机密修饰的核酸已成为预防和治疗一系列疾病的强大的新型治疗剂（例如Inclisiran，一种革命性的降胆固醇药物）。超过150项临床试验也正在进行中，使用主要类型的核酸药物，反义寡核苷酸（ASO）或小干扰RNA（siRNA），用于癌症、心血管、神经退行性疾病和感染性疾病等。与信使RNA（mRNA）杂交的（寡核苷酸），通过阻断核糖体的进展或通过核糖核酸酶（RNaseH）的募集诱导mRNA的切割来调节基因表达。siRNA是短的双链RNA分子，其与细胞中的特定蛋白质结合以形成复合物（RISC），该复合物可以切割互补的mRNA靶标。尽管它们具有巨大的潜力，但这些“神奇子弹”的生产极具挑战性，因为需要进行广泛的修饰以避免核酸酶降解并提高对mRNA靶标的亲和力。此外，它们的细胞摄取可能是有问题的，这通常需要与其他分子缀合以帮助递送。目前固相合成用于组装ASO和siRNA。然而，这需要过量的昂贵的前体（单体）、有毒试剂、有害溶剂，并且非常难以扩大规模，使得治疗昂贵并阻止新药的开发。在这个项目中，我们将开发更可持续和可扩展的酶促方法（工业生物技术），在温和的条件下，在水中，利用更良性的酶和可再生的前体提供必需的阿索和siRNA药物。(see申请表以了解更多详情）。