title: Focused Library Approach to Discover Discrete Dipeptide Bolaamphiphiles for siRNA Delivery.
abstract: In this study, we report a new dipeptide functionalization strategy for developing new dendritic bolaamphiphile vectors for efficient siRNA transfection. A focused library of dipeptides was constructed using four amino acids: l-arginine, l-histidine, l-lysine, and l-tryptophan. The dipeptides were coupled to two dendritic bolaamphiphile scaffolds that we developed previously, allowing us to quickly access a focused library of discrete vectors with multivalent dendritic dipeptide functionalities. The resulting discrete bolaamphiphiles were screened for siRNA delivery in vitro in HEK-293 and HeLa cells. Bolaamphiphiles functionalized with dipeptides containing Lys or Arg and either His or Trp were the most effective for in vitro siRNA delivery. Necessary cationic charge to ensure efficient siRNA binding are provided by Arg and Lys residues, whereas endosomal escape is provided through pH responsive buffering of His or membrane interactions of Trp. The most effective vectors (F10 HR/RH) exhibited greater than 75% gene silencing in multiple cell lines and exhibited serum stability.
authors: Department of Chemistry, University of California , Irvine, California 92697, United States.
authors: Alexander C
authors: AC
authors: Eldredge
authors: Department of Chemistry, University of California , Irvine, California 92697, United States.
authors: Mark E
authors: ME
authors: Johnson
authors: Department of Chemistry, University of California , Irvine, California 92697, United States.
authors: Nathan J
authors: NJ
authors: Oldenhuis
authors: Department of Chemistry, University of California , Irvine, California 92697, United States.
authors: Zhibin
authors: Z
authors: Guan
mesh_terms: D001120:Arginine / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008239:Lysine / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D014364:Tryptophan / Q000737:chemistry
chemical_list: D004151:Dipeptides; D005663:Furans; D011728:Pyridones; D034741:RNA, Small Interfering; C543575:bolaamphiphile; D006639:Histidine; D014364:Tryptophan; D001120:Arginine; D008239:Lysine