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

doi:10.3390/molecules27103217

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

Radboud University Nijmegen
Universidade Federal de São Paulo
Associação Beneficente de Coleta de Sangue
Radboud Institute for Molecular Life Sciences - RIMLS
Protinhi Therapeutics
Artemis Bio-Support
University of Veterinary Medicine Hannover, Foundation

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	3217
Journal	Molecules
Volume	27
Issue number	10
DOIs	https://doi.org/10.3390/molecules27103217
Publication status	Published - 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).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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Damen, M., Izidoro, M. A., Okamoto, D. N., Oliveira, L. C. G., Amatdjais-Groenen, H. I. V., van Dongen, S. F. M., van Cleef, K. W. R., van Rij, R. P., Dieteren, C. E. J., Gironés, D., van Buuren, B. N. M., Martina, B. E. E., Osterhaus, A. D. M. E., Juliano, L., Scholte, B. J., & Feiters, M. C. (2022). Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication. Molecules, 27(10), Article 3217. https://doi.org/10.3390/molecules27103217

@article{d18d92a9ab904beea8e3aea181a5388a,

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

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.",

author = "Mark Damen and Izidoro, \{Mario A.\} and Okamoto, \{Debora N.\} and Oliveira, \{Lilian C.G.\} and Amatdjais-Groenen, \{Helene I.V.\} and \{van Dongen\}, \{Stijn F.M.\} and \{van Cleef\}, \{Koen W.R.\} and \{van Rij\}, \{Ronald P.\} and Dieteren, \{Cindy E.J.\} and Daniel Giron{\'e}s and \{van Buuren\}, \{Bernd N.M.\} and Martina, \{Byron E.E.\} and Osterhaus, \{Albert D.M.E.\} and Luiz Juliano and Scholte, \{Bob J.\} and Feiters, \{Martin C.\}",

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 Cient{\'i}fico e Tecnol{\'o}gico (CNPq-Projects 471340/2011-1 and 470388/2010-2). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = may,

day = "17",

doi = "10.3390/molecules27103217",

language = "English",

volume = "27",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "10",

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Damen, M, Izidoro, MA, Okamoto, DN, Oliveira, LCG, Amatdjais-Groenen, HIV, van Dongen, SFM, van Cleef, KWR, van Rij, RP, Dieteren, CEJ, Gironés, D, van Buuren, BNM, Martina, BEE, Osterhaus, ADME, Juliano, L, Scholte, BJ & Feiters, MC 2022, 'Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication', Molecules, vol. 27, no. 10, 3217. https://doi.org/10.3390/molecules27103217

TY - JOUR

T1 - Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication

AU - Damen, Mark

AU - Izidoro, Mario A.

AU - Okamoto, Debora N.

AU - Oliveira, Lilian C.G.

AU - Amatdjais-Groenen, Helene I.V.

AU - van Dongen, Stijn F.M.

AU - van Cleef, Koen W.R.

AU - van Rij, Ronald P.

AU - Dieteren, Cindy E.J.

AU - Gironés, Daniel

AU - van Buuren, Bernd N.M.

AU - Martina, Byron E.E.

AU - Osterhaus, Albert D.M.E.

AU - Juliano, Luiz

AU - Scholte, Bob J.

AU - Feiters, Martin C.

N1 - 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). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/5/17

Y1 - 2022/5/17

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85130794501

U2 - 10.3390/molecules27103217

DO - 10.3390/molecules27103217

M3 - Article

AN - SCOPUS:85130794501

SN - 1420-3049

VL - 27

JO - Molecules

JF - Molecules

IS - 10

M1 - 3217

ER -

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

Abstract

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