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.

总部位于伦敦的生物技术中小企业Sixfold Bioscience正在开发Mergo？基于rna的递送系统，设计用于将寡核苷酸治疗药物运送到肝外组织。Mergo吗?技术允许开发一个平台，可以快速设计，以探索和筛选一个大而多样的化学空间。事实上，可以很容易地对Mergos进行化学修饰以改变其物理化学性质。Sixfold研究表明，化学成分改变的Mergos可以在体内（小鼠模型）分布到肝外组织。更有趣的是，某些Mergo？候选药物表现出细胞亲和性，为细胞特异性药物递送开辟了道路。然而，Mergo？分发到某些特定的单元还没有被处理。目前关于改变分布的主要假设是基于蛋白质指纹图谱。我们假设改变麦戈的化学特性？结果改变了生物特性（蛋白质结合物），导致分布、细胞摄取和治疗效果的差异。事实上，注射到生物液体(e_e。（血清或脑脊液），蛋白质可以结合Mergo？形成蛋白质冠。此外,Mergo吗?具有不同体内分布谱的基因，已定性显示出不同的蛋白结合谱。例如，对血清的整体亲和力发生了变化，并形成了高阶结构(蛋白质- mergo ？复合体有不同的形状和大小。SDS-PAGE分析的下拉实验显示，Mergo？候选人的身份还没有被确认。解决PB指纹图谱将有助于六倍乃至更广泛的RNAi给药领域，将化学鉴定和生物学结果联系起来。更具体地说，细胞外蛋白结合物可以用来了解体内分布，而细胞内PB可能会告知毒性和治疗活性。此外，了解蛋白质结合物是否从一个物种到另一个物种保守，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），加速临床前阶段和平台开发。最后，开发一种强大的、潜在的高通量方法来鉴定蛋白质结合物可以帮助合理设计Mergo？候选人，并集成在六倍AI/ML化学设计循环。目前，选择添加到Mergo的修改？候选物是基于ADMET小分子的性质。我们相信PB可以用来更好地预测动物在体内的行为。综上所述，蛋白结合物鉴定可用于了解作用机制（MOA）、毒性、跨物种差异，并为下一代Mergo？候选人。