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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Codominance and toxins: a path to drugs of nearly unlimited selectivity.
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Codominance and toxins: a path to drugs of nearly unlimited selectivity.

机译：共性和毒素：通往几乎无限选择性的药物的途径。

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The effectiveness of drugs is often limited by their insufficient selectivity. I propose designs of therapeutic agents that address this problem. The key feature of these reagents, termed comtoxins (codominance-mediated toxins), is their ability to utilize codominance, a property characteristic of many signals in proteins, including degradation signals (degrons) and nuclear localization signals. A comtoxin designed to kill cells that express intracellular proteins P1 and P2 but to spare cells that lack P1 and/or P2 is a multidomain fusion containing a cytotoxic domain and two degrons placed within or near two domains P1* and P2* that bind, respectively, to P1 and P2. In a cell containing both P1 and P2, these proteins would bind to the P1* and P2* domains of the comtoxin and sterically mask the nearby (appropriately positioned) degrons, resulting in a long-lived and therefore toxic drug. By contrast, in a cell lacking P1 and/or P2, at least one of the comtoxin's degrons would be active (unobstructed), yielding a short-lived and therefore nontoxic drug. A comtoxin containing both a degron and a nuclear localization signal can be designed to kill exclusively cells that contain P1 but lack P2. Analogous strategies yield comtoxins sensitive to the presence (or absence) of more than two proteins in a cell. Also considered is a class of comtoxins in which a toxic domain is split by a flexible insert containing binding sites for the target proteins. The potentially unlimited, combinatorial selectivity of comtoxins may help solve the problem of side effects that bedevils present-day therapies, for even nonselective delivery of a comtoxin would not affect cells whose protein "signatures" differ from the targeted one.
机译：药物的有效性通常受到其选择性不足的限制。我提出了解决该问题的治疗剂设计。这些试剂的主要特征，称为共毒素（共性介导的毒素），是它们利用共性的能力，共性是蛋白质中许多信号的特性，包括降解信号（degrons）和核定位信号。一种旨在杀死表达细胞内蛋白P1和P2的细胞但缺乏缺少P1和/或P2的细胞的毒素，是一种多域融合蛋白，包含细胞毒性域和位于各自结合的两个域P1 *和P2 *内或附近的两个degrons到P1和P2。在同时含有P1和P2的细胞中，这些蛋白质会结合到毒素的P1 *和P2 *结构域上，并在空间上掩盖附近的（正确放置的）德贡，从而产生长寿且因此有毒的药物。相比之下，在缺乏P1和/或P2的细胞中，至少有一种毒素会被激活（不受阻碍），从而产生寿命短且无毒的药物。可以设计同时含有降解子和核定位信号的共毒素来杀死含有P1但缺乏P2的细胞。类似策略可产生对细胞中两种以上蛋白质的存在（或不存在）敏感的毒素。还考虑了一类毒素，其中毒性结构域被包含目标蛋白结合位点的柔性插入物分开。潜在的，无限制的，组合毒素的选择性可以帮助解决困扰当今疗法的副作用问题，因为即使无选择地递送毒素也不会影响蛋白质“特征”与目标蛋白不同的细胞。

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