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These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an \u03b1-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.<\/jats:p>","DOI":"10.3390\/ijms23158322","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T20:49:28Z","timestamp":1659041368000},"page":"8322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A Second Life for MAP, a Model Amphipathic Peptide"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8164-2504","authenticated-orcid":false,"given":"Sara","family":"Silva","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-8930","authenticated-orcid":false,"given":"Kaido","family":"Kurrikoff","sequence":"additional","affiliation":[{"name":"Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia"}]},{"given":"\u00dclo","family":"Langel","sequence":"additional","affiliation":[{"name":"Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia"},{"name":"Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-4726","authenticated-orcid":false,"given":"Ant\u00f3nio J.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, s\/n, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-60761-919-2_1","article-title":"Classes and Prediction of Cell-Penetrating Peptides","volume":"Volume 683","author":"Lindgren","year":"2011","journal-title":"Methods in Molecular Biology (Clifton, N.J.)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/0092-8674(88)90263-2","article-title":"Cellular uptake of the tat protein from human immunodeficiency virus","volume":"55","author":"Frankel","year":"1988","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16010","DOI":"10.1074\/jbc.272.25.16010","article-title":"A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus","volume":"272","author":"Brodin","year":"1997","journal-title":"J. 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