Development of a Cell-penetrating Peptide that Exhibits Responsive Changes in its Secondary Structure in the Cellular Environment

作者：Yamashita Hiroko; Kato Takuma; Oba Makoto; Misawa Takashi; Hattori Takayuki; Ohoka Nobumichi; Tanaka Masakazu; Naito Mikihiko; Kurihara Masaaki^*; Demizu Yosuke^*

来源：Scientific Reports, 2016, 6(1): 33003.

DOI：10.1038/srep33003

Cell-penetrating peptides (CPP) are received a lot of attention as an intracellular delivery tool for hydrophilic molecules such as drugs, proteins, and DNAs. We designed and synthesized nona-arginine analogues 1-5 [FAM-beta-Ala-(l-Arg-l-Arg-l-Pro)(3)-(Gly)(3)-NH2 (1), FAM-beta-Ala-(l-Arg-l-Arg-l-Pro(NH2))(3)-( Gly)(3)-NH2 (2), FAM-beta-Ala-(l-Arg-l-Arg-l-Pro(Gu))(3)-(Gly)(3)-NH2 (3), FAM-beta-Ala-(l-Arg)(2)-(l-Pro(Gu))(2)-(L-Arg)(4)-L-ProGu-(Gly)(3)-NH2 (4), and FAM-beta-Ala-(l-Arg)(6)-(l-Pro(Gu))(3)-(Gly)(3)-NH2 (5)] containing l-proline (l-Pro) or cationic proline derivatives (l-ProNH(2) and l-ProGu), and investigated their cell-penetrating abilities. Interestingly, only peptide 3 having the side-chain guanidinyl l-ProGu exhibited a secondary structural change in cellular environment. Specifically, peptide 3 formed a random structure in hydrophilic conditions, whereas it formed a helical structure under amphipathic conditions. Furthermore, during cellular permeability tests, peptide 3 demonstrated greater cell-penetrating activity than other peptides and effectively transported plasmid DNA into HeLa cells. Thus, l-ProGu-containing peptide 3 may be a useful candidate as a gene delivery carrier.

• 出版日期2016-9-9