Non-Covalent Molecular Recognition for Drug Targeting in the Body

项目总结： 即使在体外验证的活性药物分子的武器库不断扩大，确保这些药物到达他们的 在限制健康组织中的毒性暴露的同时，体内理想的靶标仍然是一个挑战。 使用抗体或靶向载体靶向药物的路线仍然导致不到1%的药物到达 需要帮助的地方。与这些方法相比，分子规模的靶向可能具有固有的优势，因为 广泛的组织分布和更快地清除未结合的减毒治疗剂，导致更多 在全身毒性出现之前到达需要的部位或清除的药物。使用‘Click’化学和 相关的共价连接已经被探索用于将药物定位到预先靶点。在这里，我们描述一下我们的 开发一种通用和模块化的分子尺度方法的进展和计划 与体内所需部位的国产药物的共价亲和力。相对于共价分子尺度的方法， 我们使用的化学物质具有更快的缔合动力学，并且还可以在将来重复使用目标部位。穿过 前药方法学，我们已经证明了感兴趣的药物可以通过不稳定的亲和基序进行修饰。 连接体，通过相应结合伙伴的存在在所需的组织部位被识别。连续重启- 这些部位的剂量，或临时改变药物输送的可能性，进一步增加了我们的好处 模块化非共价方法。通过这项提议，我们寻求进一步定义这一研究计划和更多 充分利用非共价确认相对于基于“点击”的替代办法的好处。具体来说，我们将 阐明前药设计和药代动力学性质的重要性。以便能够连续地重新定位 一个药物位点-非共价识别的一个明显好处-我们将探索原位自焚的新化学 结合较低的变异体。我们还将探索这种方法，以克服常见的生理障碍 蛋白质和小分子疗法的应用，使用无毒药物的系统应用 以触发从本地应用的仓库释放带有亲和力标签的治疗性化合物。最后，为了 扩展这种靶向路线可能有用的治疗方案，我们将探索这一亲和轴 与代谢工程细胞的整合。总而言之，我们乐观地认为，新的靶向技术 我们正在开发的将释放活性物质的巨大治疗潜力，目前这些活性物质受到 全身毒性或靶点定位不良。我们正在追求的这样一个平台将会有广泛的应用 用于治疗多种疾病或用于植入生物医学的远程干预 设备练习。

PROJECT SUMMARY: Even with an ever-expanding arsenal of active drug molecules validated in vitro, ensuring these reach their desired target in the body, while at the same time limiting toxic exposure in healthy tissue, remains a challenge. Routes for targeting drugs using antibodies or targeted carriers still result in less than 1% of drug arriving at the site of need. Molecular-scale targeting may have inherent advantages relative to these approaches due to more extensive tissue distribution and more rapid clearance of unbound attenuated therapeutic agents, leading to more drug arriving at the site of need or clearing prior to onset of systemic toxicity. Routes using `click' chemistry and related covalent ligations have been explored for homing drugs to pre-targeted sites. Here, we describe our progress and plans in developing a versatile and modular molecular-scale approach that uses synthetic non- covalent affinity to home drugs to desired sites in the body. Relative to covalent molecular-scale approaches, the chemistry we use has faster kinetics of association and also enables future reuse of the targeted site. Through prodrug methodology, we have shown that drugs of interest can be modified with affinity motifs through labile linkers, to be recognized at desired tissue sites by the presence of a corresponding binding partner. Serial re- dosing of these sites, or the possibility to temporally change the drug delivered, adds further benefit to our modular non-covalent approach. With this proposal, we seek to further define this research program and more fully capture the benefits of non-covalent recognition relative to `click'-based alternatives. Specifically, we will elucidate the importance of prodrug design and pharmacokinetic properties. So as to enable serial re-targeting of a drug site – a distinct benefit of non-covalent recognition – we will explore new chemistry for in situ immolation to lower-binding variants. We will also explore this approach in overcoming common physiologic barriers to the administration of protein and small molecule therapeutics, using the systemic administration of innocuous agents to trigger the release of therapeutic compounds bearing affinity tags from locally applied depots. Finally, to expand the therapeutic scenarios wherein this targeting route may be useful, we will explore this affinity axis for integration with metabolically engineered cells. In summary, we are optimistic that the new targeting technology we are developing will unlock the vast therapeutic potential of active agents which are presently limited by systemic toxicity or poor target localization. A platform such as that we are pursuing would have broad application in therapeutic delivery for the treatment of a variety of diseases or for remote intervention in implanted biomedical device practice.