Estudo de inibidores naturais e sintéticos de cisteíno proteases

Abstract

This work describes in its first part the chemical study of the fungus Fusarium proliferatum looking for inhibitors of cysteine proteases, with two distinct approaches: i) The search for papain inhibitors, to understand the chemoecological interaction between plants rich in proteases and micro-organisms that can infect them; ii) the isolation of compounds that are possible human cysteine protease inhibitors. Nine metabolites were isolated, with beauvericin being the major compound in the extracts. This compound showed inhibitory activity against papain with IC50: 25.2 μM. In addition, beauvericin also showed inhibitory activity of two human cysteine proteases, CatV with IC50: 40.6 μM and CatB with IC50: 6.8 μM. In the second part of the study, synthetic compounds were evaluated for inhibition of cathepsin K. This enzyme is also a cysteine protease, papain-like, and is directly associated with the bone resorption process, where high CatK activity is related to bone diseases such as osteoporosis. Sixteen new synthetic compounds were evaluated, which presented moderate activities, low micro molar, against of CatK, using two approaches to search for inhibitors: i) inhibition of active site and ii) inhibition of exosites of enzyme. The compounds evaluated belong to three different classes, being epoxy-α-acyloxycarboxamide, epoxy-α-acylaminocarboxamide and quinolines phthalonitriles. An initial screening was performed to verify the activity of the inhibitors, then verified the potency of these inhibitors and the compounds that presented the best inhibitory activities were submitted to studies of the mechanisms of action. Molecular docking studies were also performed to understand the interactions between the protein and the inhibitor evaluated. The evaluated compounds showed moderate inhibitory activity, with the phononitriles being the ones with the highest potency, with IC50: 1.5 μM approximately. The compounds evaluated were identified as incompatible CatK inhibitors.