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Among strategies to increase peptide half-life (t1\/2), the use of the enantiomer (wholly made of D-amino acid residues) can be quite successful if the peptide interacts with a target in non-stereospecific fashion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>The goal of this work was the development of a more proteolytic-resistant peptide, while keeping the translocation properties. The serum stability, cytotoxicity, in vitro BBB translocation, and internalization mechanism of DPepH3 was assessed and compared to the native peptide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>DPepH3 demonstrates a much longer t1\/2 compared to PepH3. We also confirm that BBB translocation is receptor-independent, which fully validates the enantiomer strategy chosen. In fact, we demonstrate that internalization occurs trough macropinocytosis. In addition, the enantiomer demonstrates to be non-cytotoxic towards endothelial cells as PepH3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p>DPepH3 shows excellent translocation and internalization properties, safety, and improved stability. Taken together, our results place DPepH3 at the forefront of the second generation of BBB shuttles.<\/jats:p><\/jats:sec>","DOI":"10.2174\/1381612826666200213094556","type":"journal-article","created":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T16:35:01Z","timestamp":1581611701000},"page":"1495-1506","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["<sub>D<\/sub>PepH3, an Improved Peptide Shuttle for Receptor-independent Transport Across the Blood-Brain Barrier"],"prefix":"10.2174","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-9038","authenticated-orcid":true,"given":"Marco","family":"Cavaco","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6787-8286","authenticated-orcid":true,"given":"Javier","family":"Valle","sequence":"additional","affiliation":[{"name":"Proteomics and Protein Chemistry Unit, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3665-9571","authenticated-orcid":true,"given":"Ruben","family":"da Silva","sequence":"additional","affiliation":[{"name":"Centro de Ciencias e Tecnologias Nucleares and Departamento de Engenharia e Ciencias Nucleares, Instituto Superior Tecnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-4906","authenticated-orcid":true,"given":"Jo\u00e3o D.G.","family":"Correia","sequence":"additional","affiliation":[{"name":"Centro de Ciencias e Tecnologias Nucleares and Departamento de Engenharia e Ciencias Nucleares, Instituto Superior Tecnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7891-7562","authenticated-orcid":true,"given":"Miguel A. 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