Non-Covalent Molecular Recognition for Drug Targeting in the Body

项目概要： 即使有不断扩大的体外验证活性药物分子库，确保这些药物达到其 然而，如何在体内找到所需的靶点，同时限制健康组织中的毒性暴露，仍然是一个挑战。 使用抗体或靶向载体的靶向药物的途径仍然导致不到1%的药物到达靶点。 需要的地方。相对于这些方法，分子级靶向可能具有固有的优势，这是由于更高的靶向性。 广泛的组织分布和未结合的减毒治疗剂的更快清除，导致更多的 药物在全身毒性发作前到达需要或清除的部位。使用“点击”化学的路线， 已经探索了相关的共价连接以将药物导向预先靶向的位点。在这里，我们描述了我们的 在开发一种多功能和模块化分子尺度方法方面的进展和计划， 共价亲和力将药物导向体内所需部位。相对于共价分子尺度的方法， 我们使用的化学方法具有更快的结合动力学，并且还能够在将来重复使用靶位点。通过 通过前药方法，我们已经表明，感兴趣的药物可以通过不稳定的前体修饰而被亲和基序修饰。 接头，通过相应结合配偶体的存在在所需组织部位被识别。连环杀手 这些部位的给药，或暂时改变药物递送的可能性，为我们的研究增加了进一步的益处。 模块化非共价方法。有了这个建议，我们寻求进一步定义这个研究计划和更多 完全捕获非共价识别相对于基于“点击”的替代物的益处。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。以便能够连续重新瞄准 一个药物位点-非共价识别的一个明显的好处-我们将探索新的化学原位牺牲， 低结合变体。我们还将探讨这种方法在克服常见的生理障碍， 蛋白质和小分子治疗剂的施用，使用无害剂的全身施用 以触发带有亲和标记的治疗化合物从局部施用的贮库中释放。最后为 扩大这种靶向途径可能有用的治疗方案，我们将探索这种亲和轴， 与代谢工程细胞的整合。总之，我们乐观地认为，新的瞄准技术 我们正在开发的药物将释放活性药物的巨大治疗潜力， 全身毒性或靶向定位不良。我们正在寻求的这种平台将具有广泛的应用 在用于治疗各种疾病或用于植入生物医学中的远程干预的治疗递送中， 器械实践。

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.