Cationic nucleoside lipids derived from universal bases: A rational approach for siRNA transfection.
Cationic nucleoside lipids (CNLs) derived from 5-nitroindole and 4-nitroimidazole bases were prepared from d-ribose by using a straightforward chemical synthesis. TEM experiments indicate that these amphiphilic molecules self-assemble to form supramolecular organizations in aqueous solutions. Electrophoresis and standard ethidium bromide (EB) fluorescence displacement assay shows that CNLs are able to bind siRNA. We demonstrated that both the nature of the universal bases and the stereochemistry of the anomeric position (alpha, beta) have an impact on the CNLs-siRNA complex formation. Correlations among chemical structure, stereochemistry, siRNA knockdown effect, and binding affinities for all the compounds were shown and analyzed with a simple molecular modeling study. The best binding affinities for siRNA were found for the beta anomer of the 5-nitroindole CNL which exhibits protein knockdown activity similar to the standard siPORT NeoFX positive control. It is noteworthy that no significant cytotoxicity at the tested concentration was observed for the novel CNLs.
Ceballos
Claire
C
Centre Interdisciplinaire de Nanoscience de Marseille CINaM, Universite Aix-Marseille II, Luminy, France.
Khiati
Salim
S
Prata
Carla A H
CA
Zhang
Xiao-Xiang
XX
Giorgio
Suzanne
S
Marsal
Philippe
P
Grinstaff
Mark W
MW
Barthélémy
Philippe
P
Camplo
Michel
M
D001665:Binding Sites; D002412:Cations / Q000737:chemistry; D004586:Electrophoresis; D004996:Ethidium / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009593:Nitroimidazoles / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics*; D012266:Ribose / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D014162:Transfection / Q000379:methods*
D002412:Cations; D007211:Indoles; D008055:Lipids; D009593:Nitroimidazoles; D009705:Nucleosides; D034741:RNA, Small Interfering; D012266:Ribose; D004996:Ethidium; C090067:5-nitroindole; C052587:4-nitroimidazole