2. Academic Validation
  3. Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies

Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies

  • J Med Chem. 2021 Aug 26;64(16):12322-12358. doi: 10.1021/acs.jmedchem.1c01002.
Sascha Jung 1,  Natalie Fuchs 1,  Patrick Johe 1,  Annika Wagner 2,  Erika Diehl 2,  Tri Yuliani 3,  Collin Zimmer 1,  Fabian Barthels 1,  Robert A Zimmermann 1,  Philipp Klein 4,  Waldemar Waigel 5,  Jessica Meyr 5,  Till Opatz 4,  Stefan Tenzer 6,  Ute Distler 6,  Hans-Joachim Räder 7,  Christian Kersten 1,  Bernd Engels 5,  Ute A Hellmich 2 8,  Jochen Klein 3,  Tanja Schirmeister 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Biomedical Sciences (IPBS), Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
  • 2 Department of Chemistry, Biochemistry Section, Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany.
  • 3 Institute for Pharmacology and Clinical Pharmacy, Goethe University, Max-von-Laue-Str. 9, 60439 Frankfurt, Germany.
  • 4 Department of Chemistry, Organic Chemistry Section, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany.
  • 5 Department of Physical and Theoretical Chemistry, Julius-Maximilians-University, Emil-Fischer-Str. 42, 97074 Würzburg, Germany.
  • 6 Institute for Immunology, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
  • 7 Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
  • 8 Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
PMID: 34378914 DOI: 10.1021/acs.jmedchem.1c01002
Abstract

Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine Protease Inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.

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