Development of helix-stabilized cell-penetrating peptides containing cationic α, α-disubstituted amino acids as helical promoters. Issue 6 (15th March 2017)

• Record Type: Journal Article
• Authors: Yamashita, Hiroko; Misawa, Takashi; Oba, Makoto; Tanaka, Masakazu; Naito, Mikihiko; Kurihara, Masaaki; Demizu, Yosuke
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 6(2017)
• Page Start: 1846
• Page End: 1851
• Publication Date: 2017-03-15
• Subjects: Cell penetrating peptide -- α, α-disubstituted amino acid -- Helical structure -- pDNA delivery; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.01.044
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (Api C2Gu and Api C4Gu ) as helical promoters; i.e., 1 –4 [FAM-β-Ala-(l -Arg-l -Arg-Xaa)3 -(Gly)3 -NH2 (1 : Xaa = Api C2Gu, 2 : Xaa = Api C4Gu ), 3 : FAM-β-Ala-(l -Arg)8 -Api C2Gu -(Gly)3 -NH2, and4 : FAM-β-Ala-(l -Arg)5 -Api C2Gu -(l -Arg)2 -Api C2Gu -(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, peptide1, which contained three Api C2Gu 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.