Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Mario A. Izidoro
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, Brazil
Debora N. Okamoto
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, Brazil
Lilian C. G. Oliveira
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, Brazil
Helene I. V. Amatdjais-Groenen
Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Stijn F. M. van Dongen
Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Koen W. R. van Cleef
Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
Ronald P. van Rij
Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
Cindy E. J. Dieteren
Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands
Daniel Gironés
Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands
Bernd N. M. van Buuren
Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands
Byron E. E. Martina
Department of Viroscience, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands
Albert D. M. E. Osterhaus
Artemis Bio-Support, Molengraaffsingel 10, 2629 JD Delft, The Netherlands
Luiz Juliano
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, Brazil
Bob J. Scholte
Department of Cell Biology, Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands
Martin C. Feiters
Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C15H31C(O)-Lys-(Gly or Ala)nLys-NHC16H33, shorthand notation C16-KXnK-C16 with X = A or G, and n = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC50 values in the lower µM range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue.
