Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors.
Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors.
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DOI：
10.1517/17425247.2015.1082544
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发表时间：
2016
影响因子：
6.6
通讯作者：
Guo P
中科院分区：
文献类型：
--
作者：
Pi F;Vieweger M;Zhao Z;Wang S;Guo P
多重耐药性和不治之症的出现激发了对有效治疗方法的探索。我们回顾了一种通过靶向 Z>1 且 K=1 的多亚基同聚生物马达、机器或复合物来设计有效药物的新方法，其中 Z 是靶标的化学计量，K 是阻断复合物功能所需的药物亚基的数量。这种情况类似于圣诞装饰品的串联电路；一个灯泡故障会导致整个照明系统断电。在大多数多亚基、同聚生物系统中，利用顺序协调或协同作用机制，因此 K 等于 1。药物抑制取决于药物与非药物复合物的比率。当K=1且Z>1时，抑制作用遵循Z的幂律，导致药物效力增强。药物抑制效力取决于目标生物复合物的化学计量的假设最近通过 Yang-Hui 三角（或二项式分布）进行了量化，并使用高度灵敏的体外 phi29 病毒 DNA 包装系统得到了证明。讨论了针对具有高化学计量的同聚生物复合物以进行有效药物发现的示例。具有多个亚基的生物马达广泛存在于病毒、细菌和细胞中，使得该方法普遍适用于高效抑制药物的开发。
Multidrug resistance and the appearance of incurable diseases inspire the quest for potent therapeutics. We review a new methodology in designing potent drugs by targeting multi-subunit homomeric biological motors, machines, or complexes with Z>1 and K=1, where Z is the stoichiometry of the target, and K is the number of drugged subunits required to block the function of the complex. The condition is similar to a series, electrical circuit of Christmas decorations; failure of one light bulb causes the entire lighting system to lose power. In most multisubunit, homomeric biological systems, a sequential coordination or cooperative action mechanism is utilized, thus K equals 1. Drug inhibition depends on the ratio of drugged to nondrugged complexes. When K=1, and Z>1, the inhibition effect follows a power law with respect to Z, leading to enhanced drug potency. The hypothesis that the potency of drug inhibition depends on the stoichiometry of the targeted biological complexes was recently quantified by Yang-Hui's Triangle (or binomial distribution), and proved using a highly sensitive in vitro phi29 viral DNA packaging system. Examples of targeting homomeric bio-complexes with high stoichiometry for potent drug discovery are discussed. Biomotors with multiple subunits are widespread in viruses, bacteria, and cells, making this approach generally applicable in the development of inhibition drugs with high efficiency.