Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 24; pp. 5378 - 5381
• Main Authors: Wada, Shun-ichi, Takesada, Anna, Nagamura, Yurie, Sogabe, Eri, Ohki, Rieko, Hayashi, Junsuke, Urata, Hidehito
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2017; Elsevier
• Subjects: A549 Cells; Amino Acid Sequence; Aminoisobutyric Acids - chemistry; Amphipathic helical peptide; Cell-penetrating peptide (CPP); Chemistry; Chemistry, Medicinal; Chemistry, Organic; Circular Dichroism; Drug Carriers - chemistry; Fluorescent Dyes - chemistry; Fluorobenzenes - chemistry; Humans; Life Sciences & Biomedicine; Microscopy, Fluorescence; Oligopeptides - chemistry; Peptides, Cyclic - chemistry; Pharmacology & Pharmacy; Physical Sciences; RGD; RNA Interference; RNA, Small Interfering - chemistry; RNA, Small Interfering - metabolism; Science & Technology; siRNA; Structure-Activity Relationship; Transfection - methods; α-Aminoisobutyric acid (Aib); α-Aminoisobutyric acid (Aib); Cell-penetrating peptide (CPP); Amphipathic helical peptide; siRNA; RGD; DESIGN; alpha-Aminoisobutyric acid (Aib); AMINO-ACIDS; TARGETED DELIVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.11.018

Carriers for siRNA: PI: acetyl-KLULKLULKULKAULKLUGC(cRGDfC)-NH2; PII: acetyl-C(cRGDfC)KLULKLULKULKAULKLUG-NH2; PIII: acetyl-C(cRGDfC)KLULKLULKULKAULKLUGC(cRGDfC)-NH2. [Display omitted] The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure–activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells.