Seite - (000069) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.6: Cruzain inhibitor K777 and human rhinovirus 3C protease inhibitor Rupintrivir. 1.2.3.1 K777 Inhibitor Cruzain, a cysteine protease that belongs to clan CA, is a key protease required for the survival of Trypanosoma cruzi, the ethiologic agent of Chagas’ disease (McGrath, 1995; Wilkinson, 2009). For that reason, a promising group of drug leads for Chagas’ disease is cysteine protease inhibitors targeting cruzain. In 1998, McKerrow’s group reported a dipeptide vinyl sulfone, K-777 (Fig. 1.2.6), that rescued mice from a lethal Trypanosoma cruzi infection by inhibition of cruzain (Engel, 1998). Proof of mechanism came from the crystal structure of inhibitor K777 bound to cruzain, where the catalytic cysteine residue (Cys25) is covalently linked to the β-carbon of the vinylsulfone (Fig. 1.2.7). K777 was shown to be safe and efficacious in animal models of acute and chronic Chagas disease (Doyle, 2007; Barr, 2005). In particular, this vinyl sulfone protected Beagle dogs from cardiac damage during infection by T. cruzi (Barr, 2005). The results of preclinical trials showed that K777 was non- mutagenic, well-tolerated, and demonstrated efficacy in models of acute and chronic Chagas’ disease in both mice and dogs (Kerr, 2009). On the basis of these results the inhibitor entered clinical trials, but in 2013 the clinical assays were stopped due to tolerability findings at low dose in primates and dogs (http://www.dndi.org/diseases- projects/portfolio/k777.html).