半胱氨酰组织蛋白酶(CysCts)的过度活性有助于许多疾病的进展;然而,治疗抑制是有问题的。Zn2+是具有CysHis二位体或CysHis(Xaa)三位体的蛋白酶的天然抑制剂。双胍通过两个亚氨基氮形成双齿金属配合物。这里,讨论了苯乙双胍(苯乙基双胍)是募集内源性Zn2以抑制CysHis/CysHis(X)肽解的模型。苯乙双胍是一种Zn2+相互作用,活组织生物测定中的抗蛋白水解剂。苯甲酰-L-精氨酸酰胺(BAA)是木瓜蛋白酶样蛋白酶的经典底物;酰胺键是可断裂的。在这次审查中,在计算机上比较了BAA和苯乙双胍-Zn2配合物的结构。根据木瓜蛋白酶样蛋白酶的活性位点讨论了它们的化学和尺寸。两种结构的苯基部分都与许多蛋白酶典型的“S2”底物结合位点结合。当BAA的苯基部分与S2结合时,可断裂的酰胺键指向硫醇盐-咪唑鎓离子对的位置,然后水解。然而,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。苯乙双胍稳定药物和蛋白酶活性位点之间的“Zn2+三明治”。已经在1和5个氮位置合成了数百种双胍衍生物;可以想到更多。各种取代基部分可以与底物结合位点的各种阵列配准,以便将配位的Zn2+与不同蛋白酶的催化配偶体比对。双胍在此被鉴定为用于合成具有宽范围的效力和特异性的治疗性CysCt抑制剂的可修饰的药效团。苯乙双胍-Zn2+配合物。
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.