New peptidomimetic rhodesain inhibitors with improved selectivity towards human cathepsins

• Published in: European journal of medicinal chemistry 2022-08, Vol.238, p.114460-114460, Article 114460
• Main Authors: Jung, Sascha, Fuchs, Natalie, Grathwol, Christoph, Hellmich, Ute A., Wagner, Annika, Diehl, Erika, Willmes, Thomas, Sotriffer, Christoph, Schirmeister, Tanja
• Format: Article
• Language: English
• Subjects: Cathepsins; de-novo design; Inhibitors; Molecular docking; Rhodesain; Trypanosomes
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114460

Parasitic cysteine proteases such as rhodesain (TbCatL) from Trypanosoma brucei rhodesiense are relevant targets for developing new potential drugs against parasitic diseases (e. g. Human African Trypanosomiasis). Designing selective inhibitors for parasitic cathepsins can be challenging as they share high structural similarities with human cathepsins. In this paper, we describe the development of novel peptidomimetic rhodesain inhibitors by applying a structure-based de novo design approach and molecular docking protocols. The inhibitors with a new scaffold in P2 and P3 position display high selectivity towards trypanosomal rhodesain over human cathepsins L and B and high antitrypanosomal activity. Vinylsulfonate 2a has emerged as a potent rhodesain inhibitor (k2nd = 883 • 103 M−1 s−1) with single-digit nanomolar binding affinity (Ki = 9 nM) and more than 150-fold selectivity towards human cathepsins and it thus constitutes an interesting starting compound for the further development of selective drugs against Human African Trypanosomiasis. [Display omitted] •A de novo approach was applied to design new peptidomimetic rhodesain inhibitors.•The new scaffold to address the S2 and S3 pockets improves the selectivity towards human cathepsins.•Compound 2a displays single-digit nanomolar affinity for rhodesain and high selectivity.•The inhibitors display antitrypanosomal activity in the low micromolar range.