Proteases: How naturally occurring inhibitors can facilitate small molecule drug discovery for cysteine proteases

20 August 2013  •  Author(s): Sheraz Gul, Vice President and Head of Biology, European ScreeningPort GmbH

Cysteine proteases are expressed ubiquitously in the animal and plant kingdom and are thought to play key roles in maintaining homeostasis. The aberrant function of cysteine proteases in humans are known to lead to a variety of epidermal disease states such as inflammatory skin disease1. In marked contrast, the serine proteases have been most widely implicated in disease states, including hypertension, periodontisis, AIDS, thrombosis, respiratory disease, pancreatitis and cancer2, and a number of their inhibitors have been approved for clinical use.

Details of protease inhibitors in clinical use have been reviewed and referenced by Abbenante & Fairlie3 and up-to-date information relating to clinical trials for a wide range of diseases, including those that involve protease inhibitors can be identified using the National Institutes of Health clinical trial database ( which currently contains >100,000 clinical trials from 180 countries and receives over 50 million page views per month. Despite the successes in discovering and developing orally administered protease inhibitors, significant challenges still remain with regards to their safety profiles and demonstrable efficacy in clinical trials. Nevertheless, the fact that there are small molecule protease inhibitors undergoing clinical trials confirms the view that the protease target class are tractable for drug discovery4. In this article, the roles of synthetic, natural products and endogenous cystatin M/E are discussed, in particular with respect to facilitating cysteine protease small molecule drug discovery.

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