Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn2+ is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. Biguanide forms bidentate metal complexes through the two imino nitrogens. Here, it is discussed that phenformin (phenylethyl biguanide) is a model for recruitment of endogenous Zn2+ to inhibit CysHis/CysHis(X) peptidolysis. Phenformin is a Zn2+-interactive, anti-proteolytic agent in bioassay of living tissue. Benzoyl-L-arginine amide (BAA) is a classical substrate of papain-like proteases; the amide bond is scissile. In this review, the structures of BAA and the phenformin-Zn2+ complex were compared in silico. Their chemistry and dimensions are discussed in light of the active sites of papain-like proteases. The phenyl moieties of both structures bind to the "S2" substrate-binding site that is typical of many proteases. When the phenyl moiety of BAA binds to S2, then the scissile amide bond is directed to the position of the thiolate-imidazolium ion pair, and is then hydrolyzed. However, when the phenyl moiety of phenformin binds to S2, then the coordinated Zn2+ is directed to the identical position; and catalysis is inhibited. Phenformin stabilizes a "Zn2+ sandwich" between the drug and protease active site. Hundreds of biguanide derivatives have been synthesized at the 1 and 5 nitrogen positions; many more are conceivable. Various substituent moieties can register with various arrays of substrate-binding sites so as to align coordinated Zn2+ with catalytic partners of diverse proteases. Biguanide is identified here as a modifiable pharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range of potencies and specificities. Phenformin-Zn2+ Complex.

中文翻译：

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双胍是可修饰的药效基团，用于募集内源性Zn2 +以抑制半胱氨酸组织蛋白酶：综述和意义。

半胱氨酸组织蛋白酶（CysCts）的过度活动导致许多疾病的发展；然而，治疗抑制是有问题的。Zn2 +是与CysHis二联体或CysHis（Xaa）三联体蛋白酶的天然抑制剂。双胍通过两个亚氨基形成二齿金属络合物。在这里，讨论了苯乙双胍（苯乙双胍）是内源性Zn2 +募集以抑制CysHis / CysHis（X）肽分解的模型。苯乙双胍是在活组织生物测定中与Zn2 +相互作用的抗蛋白水解剂。苯甲酰基-L-精氨酸酰胺（BAA）是木瓜蛋白酶样蛋白酶的经典底物；酰胺键易裂。在这篇综述中，通过计算机比较了BAA和苯乙双胍-Zn2 +复合物的结构。根据木瓜蛋白酶样蛋白酶的活性位点讨论了它们的化学性质和尺寸。两个结构的苯基部分都结合了许多蛋白酶典型的“ S2”底物结合位点。当BAA的苯基部分与S2结合时，可裂开的酰胺键被引导至硫醇盐-咪唑鎓离子对的位置，然后被水解。但是，当苯乙双胍的苯基部分与S2结合时，则配位的Zn2 +指向相同的位置。并且催化被抑制。苯乙双胍可稳定药物和蛋白酶活性位点之间的“ Zn2 +三明治”。在1和5个氮原子位置上已合成了数百个双胍衍生物。可以想象更多。各种取代基部分可与底物结合位点的各种阵列配准，以使配位的Zn2 +与各种蛋白酶的催化配偶体对齐。双胍在这里被鉴定为可合成的药效基团，用于合成具有广泛效价和特异性的治疗性CysCt抑制剂。苯乙双胍-Zn2 +复合物。