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

Mark Damen, Mario A. Izidoro, Debora N. Okamoto, Lilian C.G. Oliveira, Helene I.V. Amatdjais-Groenen, Stijn F.M. van Dongen, Koen W.R. van Cleef, Ronald P. van Rij, Cindy E.J. Dieteren, Daniel Gironés, Bernd N.M. van Buuren, Byron E.E. Martina, Albert D.M.E. Osterhaus, Luiz Juliano*, Bob J. Scholte, Martin C. Feiters*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number3217
JournalMolecules
Volume27
Issue number10
DOIs
Publication statusPublished - 17 May 2022

Bibliographical note

Funding: The research was funded by the Dutch Technology Foundation STW (now TTW, MD/MF/BS, nac.6565) and in part by the European 6th Framework program IMPROVED PRECISION LSHB-CT-2004-005213 (BS), the Dutch CF Foundation NCFS (BS), the Netherlands Organisation for Scientific Research (NWO-NGO PreSeed grant 9363001), the European Union/provinces of Gelderland and Overijssel (EFRO Tropinhi, PROJ-00672), and the Brazilian research agencies (MI, LJ) (FAPESP-Project 12/50191-4R), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Projects 471340/2011-1 and 470388/2010-2).

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© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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