Enhancement of the inhibitory activity of oatp antisense oligonucleotides by incorporation of 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) without a loss of subtype selectivity.
Antisense oligonucleotides (AONs) that specifically target the genes of rat organic anion transporting polypeptide (oatp) subtypes were selected by using antisense in vitro selection (AIVS) and a conventional gene alignment program (GAP). When we incorporated several of our original 2'-O,4'-C-ethylene-bridged nucleic acid (ENA) residues into AONs, which were designed as gapmers containing a series of 2'-deoxynucleotides in the center, at both the 3' and 5' ends, the inhibitory activity of these oatp AONs was enhanced and their inhibition was mediated by RNase H cleavage. Moreover, these ENA AONs did not lose their oatp selectivity. These strategies of using AIVS and GAP to select AONs followed by incorporation of ENA residues were effective for synthesizing oatp subtype-specific AONs.
Takagi
Miho
M
Lead Discovery Research Laboratories, Sankyo Company, Ltd., 2-58, Hiromachi 1-Chome, Shinagawa-ku, Tokyo 140-8710, Japan.
Morita
Koji
K
Nakai
Daisuke
D
Nakagomi
Rie
R
Tokui
Taro
T
Koizumi
Makoto
M
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000235:genetics; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D005030:Ethylenes / Q000138:chemical synthesis* / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment / Q000379:methods; D013873:Thionucleotides / Q000138:chemical synthesis / Q000378:metabolism; D014982:Xenopus laevis
D001952:Bridged-Ring Compounds; D005030:Ethylenes; D009705:Nucleosides; D016376:Oligonucleotides, Antisense; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C421102:Slco1a1 protein, rat; C421143:Slco1a5 protein, rat; C451262:Slco1c1 protein, rat; D013873:Thionucleotides