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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\u20132). 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 \u00b5M range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 \u00b5M) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 \u00b5M) 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.<\/jats:p>","DOI":"10.3390\/molecules27103217","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T03:20:43Z","timestamp":1652844043000},"page":"3217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication"],"prefix":"10.3390","volume":"27","author":[{"given":"Mark","family":"Damen","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Izidoro","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo (UNIFESP), Rua Tr\u00eas de Maio, 100, S\u00e3o Paulo 04044-020, Brazil"},{"name":"Laboratory of Spectrometry, Beneficent Association of Blood Collection, Associa\u00e7\u00e3o Beneficente de Coleta de Sangue (COLSAN), Av. Jandira 1260, S\u00e3o Paulo 04080-006, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo (UNIFESP), Rua Tr\u00eas de Maio, 100, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5117-6979","authenticated-orcid":false,"given":"Lilian","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo (UNIFESP), Rua Tr\u00eas de Maio, 100, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Amatdjais-Groenen","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"van Dongen","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"van Cleef","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-4689","authenticated-orcid":false,"given":"Ronald","family":"van Rij","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Dieteren","sequence":"additional","affiliation":[{"name":"Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Giron\u00e9s","sequence":"additional","affiliation":[{"name":"Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"van Buuren","sequence":"additional","affiliation":[{"name":"Protinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron","family":"Martina","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands"},{"name":"Artemis Bio-Support, Molengraaffsingel 10, 2629 JD Delft, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-3497","authenticated-orcid":false,"given":"Albert","family":"Osterhaus","sequence":"additional","affiliation":[{"name":"Artemis Bio-Support, Molengraaffsingel 10, 2629 JD Delft, The Netherlands"},{"name":"Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5589-2822","authenticated-orcid":false,"given":"Luiz","family":"Juliano","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo (UNIFESP), Rua Tr\u00eas de Maio, 100, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"Scholte","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands"},{"name":"Pediatric Pulmonology, Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Feiters","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/nrmicro2460","article-title":"Dengue: A continuing global threat","volume":"8","author":"Guzman","year":"2010","journal-title":"Nat. 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