Title
Development of helix-stabilized cell-penetrating peptides containing cationic α,α-disubstituted amino acids as helical promoters
Author
Hiroko Yamashita, Takashi Misawa, Makoto Oba, Masakazu Tanaka, Mikihiko Naito, Masaaki Kurihara, Yosuke Demizu
Year
2017
Journal
Bioorganic & Medicinal Chemistry
Abstract
Cell-penetrating peptides (CPP) have attracted many scientists’ attention as intracellular delivery tools due to their high cargo molecule transportation efficiency and low cytotoxicity. Therefore, in many research fields CPP, such as HIV-Tat and oligoarginine (Rn), are used to deliver hydrophilic drugs and biomolecules, including proteins, DNA, and RNA. We designed four types of CPP that contained cationic α,α-disubstituted amino acids (ApiC2Gu and ApiC4Gu) as helical promoters; i.e., 1–4 [FAM-β-Ala-(l-Arg-l-Arg-Xaa)3-(Gly)3-NH2 (1: Xaa = ApiC2Gu, 2: Xaa = ApiC4Gu), 3: FAM-β-Ala-(l-Arg)8-ApiC2Gu-(Gly)3-NH2, and 4: FAM-β-Ala-(l-Arg)5-ApiC2Gu-(l-Arg)2-ApiC2Gu-(Gly)3-NH2], and investigated their preferred secondary structures and cell membrane-penetrating ability. As a result, we found that the permeation efficiency of the CPP was affected by the number of helical promoters in their sequences. Specially, peptide 1, which contained three ApiC2Gu residues, formed a stable helical structure and passed through the cell membrane more efficiently than the other peptides. Moreover, it was demonstrated that the spatial arrangement of the peptides’ side chains also influenced their permeability and the helical stabilization of their main chains.
Instrument
J-720
Keywords
Circular dichroism, Secondary structure, Chemical stability, Biochemistry, Medicinal