PLoS Neglected Tropical Diseases (Mar 2020)

Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.

  • Lorenzo Cianni,
  • Carina Lemke,
  • Erik Gilberg,
  • Christian Feldmann,
  • Fabiana Rosini,
  • Fernanda Dos Reis Rocho,
  • Jean F R Ribeiro,
  • Daiane Y Tezuka,
  • Carla D Lopes,
  • Sérgio de Albuquerque,
  • Jürgen Bajorath,
  • Stefan Laufer,
  • Andrei Leitão,
  • Michael Gütschow,
  • Carlos A Montanari

DOI
https://doi.org/10.1371/journal.pntd.0007755
Journal volume & issue
Vol. 14, no. 3
p. e0007755

Abstract

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The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.