Investigation into the P₃ Binding Domain of m-Calpain Using Photoswitchable Diazo- and Triazene-dipeptide Aldehydes:  New Anticataract Agents

Abstract

The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a-d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S3 pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC50 of 35 nM). The diazo-containing inhibitors 8a, 8c, and 10a were irradiated at 340 nm to give a photostationary state enriched in the (Z)-isomer, and in all cases, these were less active. The most water soluble triazene 17a (IC50 of 90 nM) retards calpain-induced cataract formation in lens culture.

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

“…(5), [165,168,171]) inhibitors show an extended or -strand conformation for the inhibitor backbone, which is observed in almost all inhibitor-protease interactions [172,173]. This conformation is defined by three key hydrogen bonds: between the NH and carbonyl groups of the P 2 residue of the inhibitor (nomenclature according to Schechter and Berger [174]) and Gly208 (calpain 1 numbering) of I-II and also between the NH of the P 1 -P 2 amide bond and I-II's Gly271 [175]. This characteristic hydrogen bond pattern is clearly evident in the structures of I-II in complex with AK-295-D2 (shown in Fig.…”

Photochromic Materials in Biochemistry

“…Therefore, this enzyme class is an important target for treating malignancies, as evidenced by several proteasome inhibitors available for treatment of cancers. A number of examples illustrating the photoregulation of proteasomes using azobenzene-derived inhibitors have been developed to date [35,40,41,46,47]. Recently, a photoswitchable protease inhibitor, inspired by the clinically approved chemotherapy drug bortezomib, was developed [42].…”

Role of proteases in the development and diseases of the lens

“…Therefore, calpain inhibitors could act as potent anticataract agents [56]. For example, m-calpain-specific inhibitors are currently under development and their efficacy as anti-cataract agents is being tested [58].…”