Engineering Triggered Nanomechanical Therapeutics

项目摘要：工程触发纳米机械治疗 这项研究的目标是为新的治疗范例发展分子基础。 基于使用合成核酸设备触发的纳米机械转导。传统药物可能是 被认为是专门与靶分子结合的结构治疗学，该靶分子既是 疾病和治疗疾病的方法。如果目标不特定于，则此双重角色是不可取的 病态细胞(例如癌症化疗的毒副作用)，或者如果靶点不是这样的话限制 促进有效治疗。 在这里，我们建议发展“机械”疗法，其中治疗领域的活动是在 独立诊断结构域的机械控制：当且仅当诊断结构域与其目标绑定 (由于其作为疾病标志物的特异性而被选择)，最初不活跃的治疗域切换到激活的 能够与第二个不相关的靶点结合的构象(选择是因为它有效地激活了治疗性 路径)。使用不同的诊断和治疗领域允许独立优化特异性和 在这些结构域之间引入触发的机械转导提供了积极的抑制- 在分子水平上得到阳性诊断(将副作用降至最低)之前，监测药物的活性。 机械转导也提供了实现基本分子逻辑的灵活性，允许触发 基于多个疾病标志物的诊断后的激活。 这种动态功能将被编码在治疗性RNA分子序列中，这些分子相互作用并 改变构象以实施两种概念上强大的治疗策略： 如果检测到基因A，则通过触发的RNA干扰使基因B沉默。 如果检测到A基因，通过触发免疫反应杀死细胞。 在这两种情况下，关键点都是药物的活性(即基因沉默或细胞死亡)是由 检测到一个无关的疾病标志物。 触发纳米机械转导的概念暗示了潜在的变革性治疗策略-- GES用于治疗多种疾病，包括癌症、多发性硬化症等自身免疫性疾病、 以及登革热等由莫斯奎特传播的病毒感染。我们目前的目标是展示 通过强有力地触发哺乳动物细胞中的基因沉默和细胞死亡的纳米机械转导，提供 一项原则证明，以激励对这一新治疗概念的进一步探索。 1

Project Summary: Engineering Triggered Nanomechanical Therapeutics The goal of this program of research is to develop the molecular foundations for a new therapeutic paradigm based on triggered nanomechanical transduction using synthetic nucleic acid devices. Traditional drugs may be viewed as 'structural therapeutics' that bind specifically to a target molecule that serves as both the marker for the disease and the means of treating the disease. This dual role is undesirable if the target is not specific to diseased cells (exemplified by toxicity side effects with cancer chemotherapies), or limiting if the target does not facilitate potent treatment. Here, we propose to develop 'mechanical' therapeutics in which the activity of the treatment domain is under the mechanical control of an independent diagnosis domain: if and only if the diagnosis domain binds to its target (selected for its specificity as a disease marker), the initially inactive treatment domain switches to an activated conformation capable of binding to a second unrelated target (selected for its potent activation of a therapeutic pathway). The use of distinct diagnosis and treatment domains allows independent optimization of specificity and potency; the introduction of triggered mechanical transduction between these domains provides active suppres- sion of the drug's activity until a positive diagnosis is achieved at the molecular level (minimizing side effects). Mechanical transduction also provides the flexibility to implement elementary molecular logic, permitting triggered activation following diagnosis based on multiple disease markers. This dynamic functionality will be encoded in the sequences of therapeutic RNA molecules that interact and change conformation to implement two conceptually powerful therapeutic strategies: If gene A is detected, silence gene B via triggered RNA interference. If gene A is detected, kill the cell via triggered immune response. In both cases, the key point is that the activity of the drug (i.e., gene silencing or cell death) is triggered by the detection of an unrelated disease marker. The concept of triggered nanomechanical transduction suggests potentially transformative therapeutic strate- gies for treating broad classes of disease, including cancers, autoimmune diseases such as multiple sclerosis, and mosquite-borne viral infections such as dengue fever. Our current objective is to demonstrate the promise of nanomechanical transduction by robustly triggering gene silencing and cell death in mammalian cells, providing a proof-of-principle to motivate further exploration of this new therapeutic concept. 1