Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication

Molecules

Albert D. M. E. Osterhaus¹  Luiz Juliano²  Mario A. Izidoro²  Lilian C. G. Oliveira²  Debora N. Okamoto²  Bob J. Scholte³  Koen W. R. van Cleef⁴  Ronald P. van Rij⁴  Stijn F. M. van Dongen⁵  Helene I. V. Amatdjais-Groenen⁵  Mark Damen⁵  Martin C. Feiters⁵  Byron E. E. Martina⁶  Cindy E. J. Dieteren⁷  Bernd N. M. van Buuren⁷  Daniel Gironés⁷ 

[1] Artemis Bio-Support, Molengraaffsingel 10, 2629 JD Delft, The Netherlands;Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, Brazil;Department of Cell Biology, Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands;Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands;Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands;Department of Viroscience, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands;Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands;

关键词: amphiphiles;    drug discovery;    inhibitors;    membrane proteins;    peptides;   

DOI  :  10.3390/molecules27103217

来源: DOAJ

【 摘 要 】

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-KX_nK-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.

【 授权许可】

Unknown