Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn(2+) to inhibit cysteinyl cathepsins: review and implications

ABSTRACT: Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn(2+) 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 Zn(2+) to inhibit CysHis/CysHis(X) peptidolysis. Phenformin is a Zn(2+)-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-Zn(2+) 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 Zn(2+) is directed to the identical position; and catalysis is inhibited. Phenformin stabilizes a “Zn(2+) 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 Zn(2+) 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. GRAPHICAL ABSTRACT: Phenformin-Zn(2+) Complex [Image: see text]