Novel BChE inhibitors have been prepared using a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. This compound represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease and cancer.
COBISS.SI-ID: 3713393
Cathepsin B has an important role in the development and progression of cancer. It is unique among cathepsins in possessing both carboxypeptidase and endopeptidase activities, the the latter being involved in pathological degradation of the extracellular matrix. Its activities are regulated by different means, the most important being its endogenous inhibitors, the cystatins. In cancer this peptidase/inhibitor balance is altered, leading to harmful cathepsin B activity. The latter can be prevented by exogenous inhibitors. They differ in modes of inhibition, size, structure, binding affinity, selectivity, toxicity and bioavailability. In this article, we review the properties and function of endogenous and exogenous cathepsin B inhibitors and indicate their application as possible anticancer agents.
COBISS.SI-ID: 3730545
The research paper describes unusual properties of cysteine carboxypeptidase cathepsin X in malignant processes. It presents molecular targets, degraded by this protease and mechanisms, leading to progression of the disease. Contrary to other lysosomal proteases cathepsin X does not degrade extracellular matrix but promote tumour progression through regulation of integrin receptors, gamma-enolase, chemokine CXCL-12, bradykinin, kallidin, huntingtin and profilin 1. In particular, its role is important when the activity of other proteases is inactivated. In this case its expression is increased enabling alternative pathway of tumour proteolysis. This discovery is important if protease inhibitors are used in antitumour therapy.
COBISS.SI-ID: 3650929