Exploring druggable hot spots in Schistosoma mansoni cathepsin B1 for structure-based design of vinyl sulfone inhibitors

Adela Jilkova¹, Petra Rubesova¹, Pavlina Rezacova¹, Jindrich Fanfrlik¹, Pavla Fajtova¹, Jiri Brynda¹, Martin Lepsik¹, Martin Horn¹, James H. McKerrow², Conor R. Caffrey², and Michael Mares¹

¹Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, Prague, 16610, Czech Republic, jilkova@uochb.cas.cz, rubesova@uochb.cas.cz

2Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

Schistosomiasis, caused by parasitic blood flukes of the genus Schistosoma, afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins and is a drug target for vinyl sulfone inhibitors. We present a detailed inhibition profiling of SmCB1 with a set of vinyl sulfone peptidomimetic derivatives. They were screened against recombinant SmCB1 and against S. mansoni schistosomulas. This work provided two inhibitors of SmCB1 with the IC₅₀ values in the sub-nanomolar range that are the most effective inhibitors of this enzyme reported to date. Their high resolution crystal structures in complex with SmCB1 were determined. Analysis of the inhibitor binding mode using quantum chemical calculations identified novel interaction hot spots that can be exploited for the rational design of anti-schistosomal chemotherapeutics.

This work was supported by the grant LH15040 and the project InterBioMed LO1302 from the Ministry of Education, Youth and Sports of the Czech Republic and the institutional project RVO 61388963.