Pharmacognosy, Phytochemistry & Natural Products

Biography

Biography: Dieter Brömme

Abstract

Cysteine cathepsins are potent extracellular matrix-degrading proteases that have been implicated in various skeletal, vascular, and respiratory pathologies. Highly potent active site-directed inhibitors have been developed and tested in preclinical and clinical studies. Whereas they are highly effective in slowing down the destructive matrix degradation process, they also have serious side effects, which can be attributed to the inhibition of the regulatory functions of the target protease. We have developed a strategy where only the pathologically relevant degradation of collagen and elastin is inhibited without interfering with the other proteolytic functions of the protease. These inhibitors are named ectosteric inhibitors, which bind outside of the active site and either block the binding of therapeutically relevant substrates, ligand binding and/or protease oligomerization needed for the degradation of extracellular matrix proteins. Natural product libraries appear to be a rich source of such inhibitors. Using various plant extracts and purified compound libraries, we identified potent ectosteric inhibitors, which specifically inhibit the collagenase and elastase activities of cathepsins. The talk will discuss the strategy of the identification of ectosteric inhibitors, their mechanism, and efficacy in in vivo models. Emphasis will be given to compounds identified in traditional Chinese Herbal Medicine used in skeletal ands cardiovascular diseases.