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Dengue epidemics now reach temperate regions due to globalization of trade and travel and climate changes. Currently, there are no successful therapeutic or preventive approaches. We previously developed a peptide drug lead, pep14-23, that inhibits the biologically relevant interaction of DENV capsid (C) protein with lipid droplets (LDs). Surprisingly, pep14-23 also inhibits DENV C interaction with very low-density lipoproteins (VLDL). We thus investigated the similarity between the proposed DENV C molecular targets in LDs and VLDL, respectively, the proteins perilipin 3 (PLIN3) and apolipoprotein E (APOE). APOE N-terminal and PLIN3 C-terminal regions are remarkably similar, namely APOE \u03b1-helix 4 (APOE\u03b14) and PLIN3 \u03b1-helix 5 (PLIN3\u03b15) sequences, which are also highly superimposable structurally. Interestingly, APOE \u03b1-helical N-terminal sequence and structure superimposes with DENV C \u03b1-helices \u03b11 and \u03b12. Moreover, the DENV C hydrophobic cleft can accommodate the structurally analogous APOE\u03b14 and PLIN3\u03b15 helical regions. Mirroring DENV C-LDs interaction (previously shown experimentally to require PLIN3), we experimentally demonstrated that DENV C-VLDL interaction requires APOE. Thus, the results fit well with previous data and suggest future drug development strategies targeting the above mentioned \u03b1-helical structures.<\/jats:p>","DOI":"10.1038\/srep10592","type":"journal-article","created":{"date-parts":[[2015,7,10]],"date-time":"2015-07-10T12:32:30Z","timestamp":1436531550000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Understanding Dengue Virus Capsid Protein Interaction with Key Biological Targets"],"prefix":"10.1038","volume":"5","author":[{"given":"Andr\u00e9 F.","family":"Faustino","sequence":"first","affiliation":[]},{"given":"Ivo C.","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Filomena A.","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Miguel A. R. 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