Investigation of Mergo? mechanism of action by quantitative serum protein profiling.

调查梅尔戈？

• 批准号: 10074412
• 金额: $ 1.15万
• 依托单位: SIXFOLD BIOSCIENCE LTD.
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=10074412
• 关键词: Investigation; Mergo; mechanism; action; quantitative

Sixfold Bioscience, a London-based biotech SME, are developing Mergo?, RNA-based delivery systems designed to carry oligonucleotides therapeutics to extrahepatic tissues. The Mergo? technology allows the development of a platform that can rapidly be engineered to explore and screen a large and diverse chemical space. Indeed, Mergos can be easily chemically modified to change their physicochemical properties. Sixfold has shown that Mergos with altered chemical composition can distribute to extrahepatic tissues _in vivo_ (mice models). More interestingly, certain Mergo? candidates display cell tropism, opening the way to cell-specific drug delivery. Yet, the mechanism by which Mergo? distribute to certain cells specifically has not been addressed. The current leading hypothesis for altered distribution is based on protein fingerprinting.We postulate that modifying the chemical identities of Mergo? results in altered biological identity (protein binders), leading to differences in distribution, cellular uptake and therapeutic effect. Indeed, upon injection to biological fluids (_e.g_ serum or cerebral spinal fluid), proteins are shown to bind Mergo?, forming a protein corona. Moreover, Mergo? with different _in vivo_ distribution profiles have been qualitatively shown to display different protein binding (PB) profiles. For example, whole affinity to serum changed, and the higher-order structures formed (protein-Mergo? complexes) have different shapes and sizes.While pulldown experiments analyzed by SDS-PAGE have revealed that protein binders differ between Mergo? candidates, their identities have not been yet elucidated. Resolving PB fingerprints would help Sixfold, and more globally the RNAi drug delivery field, to link chemical identity and biological outcomes. More specifically, the extracellular protein binders can be used to understand _in vivo_ distribution, while intracellular PB might inform on toxicity and therapeutic activity. Additionally, understanding whether protein binders are conserved from one species to another would help understanding whether results observed in small animals (mouse) can be translated to bigger species (NHP, human), accelerating preclinical phase and platform development. Finally, the development of a robust, potentially high-throughput method to identify protein binders could help to rationally design Mergo? candidates, and be integrated within the Sixfold AI/ML chemical design loop. Currently, the choice of the modifications added to Mergo? candidates is based on ADMET properties of small molecules. We believe that PB can be used to better predict _in vivo_ behaviour. In summary, protein binders identification could be used to understand mechanism of action (MOA), toxicity, cross-species differences and inform better the design of next-generation Mergo? candidates.

Sixfold Bioscience 是一家总部位于伦敦的生物技术中小企业，正在开发基于 RNA 的 Mergo® 递送系统，旨在将寡核苷酸治疗药物运送到肝外组织。梅尔戈？技术允许开发一个可以快速设计的平台，以探索和筛选大型且多样化的化学空间。事实上，Mergos 可以很容易地进行化学修饰以改变其物理化学性质。 Sixfold 已表明，化学成分发生改变的 Mergos 可以在体内分布到肝外组织（小鼠模型）。更有趣的是，某些 Mergo？候选药物表现出细胞向性，为细胞特异性药物输送开辟了道路。然而，Mergo 的机制是什么？具体分配给某些细胞尚未得到解决。目前关于改变分布的主要假设是基于蛋白质指纹分析。我们假设改变 Mergo 的化学特性？导致生物特性（蛋白质结合剂）改变，从而导致分布、细胞摄取和治疗效果的差异。事实上，在注射到生物体液（例如血清或脑脊液）后，蛋白质会与 Mergo? 结合，形成蛋白质冠。而且，梅尔戈？已定性地显示具有不同_体内_分布概况的蛋白质显示出不同的蛋白质结合（PB）概况。例如，对血清的整体亲和力发生了变化，形成的高级结构（蛋白质-Mergo? 复合物）具有不同的形状和大小。而通过 SDS-PAGE 分析的下拉实验表明，Mergo? 之间的蛋白质结合剂不同。候选人的身份尚未查明。解决 PB 指纹将有助于 Sixfold 以及全球范围内的 RNAi 药物输送领域将化学特性和生物学结果联系起来。更具体地说，细胞外蛋白结合剂可用于了解体内分布，而细胞内 PB 则可了解毒性和治疗活性。此外，了解蛋白质结合剂在一个物种到另一个物种之间是否保守，将有助于了解在小动物（小鼠）中观察到的结果是否可以转化为更大的物种（NHP，人类），从而加速临床前阶段和平台开发。最后，开发一种稳健的、潜在高通量的方法来识别蛋白质结合剂可能有助于合理设计 Mergo?候选者，并集成到 Sixfold AI/ML 化学设计循环中。目前，Mergo 添加了哪些修改选项？候选物是基于小分子的 ADMET 特性。我们相信 PB 可用于更好地预测_体内_行为。总之，蛋白质结合剂鉴定可用于了解作用机制 (MOA)、毒性、跨物种差异，并更好地为下一代 Mergo? 的设计提供信息。候选人。