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

Overview

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.

authors

  • Jung, Sascha
  • Fuchs, Natalie Sabrina
  • Johe, Patrick
  • Wagner, Annika
  • Diehl, Erika
  • Yuliani, Tri
  • Zimmer, Collin
  • Barthels, Fabian
  • Zimmermann, Robert A
  • Klein, Philipp
  • Waigel, Waldemar
  • Meyr, Jessica
  • Opatz, Till
  • Tenzer, Stefan
  • Distler, Ute
  • Räder, Hans-Joachim
  • Kersten, Christian
  • Engels, Bernd
  • Hellmich, Ute A
  • Klein, Jochen
  • Schirmeister, Tanja

publication date

  • August 11, 2021

Research

keywords

  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors
  • Sulfones
  • Sulfonic Acids
  • Trypanocidal Agents
  • Vinyl Compounds

Identity

Scopus Document Identifier

  • 85113873829

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.1c01002

PubMed ID

  • 34378914

Additional Document Info

volume

  • 64

issue

  • 16