Identification of non-peptidic cysteine reactive fragments as inhibitors of cysteine protease rhodesain

Abstract

Rhodesain, the major cathepsin L-like cysteine protease in the protozoan Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness, is a well-validated drug target. In this work, we used a fragment-based approach to identify inhibitors of this cysteine protease, and identified inhibitors of T. brucei. To discover inhibitors active against rhodesain and T. brucei, we screened a library of covalent fragments against rhodesain and conducted preliminary SAR studies. We envision that in vitro enzymatic assays will further expand the use of the covalent tethering method, a simple fragment-based drug discovery technique to discover covalent drug leads.

Keywords: Covalent fragments; Cysteine protease; Rhodesain; Trypanosomes.

Figure 1

Inhibitors of rhodesain that have antitrypanosomal activity.

Figure 2

Inhibitors of rhodesain from this study.

Figure 3

Pseudo-first order and second-order inhibition plots for compounds 5, 6 and 7.

Scheme 1

Overview of rhodesain-fragment conjugation.