Biologically active oligodeoxyribonucleotides. 5. 5'-End-substituted d(TGGGAG) possesses anti-human immunodeficiency virus type 1 activity by forming a G-quadruplex structure.
A series of hexadeoxyribonucleotides (6-mers), d(TGGGAG), substituted with a variety of aromatic groups at the 5'-end were synthesized and tested for anti-human immunodeficiency virus type 1 (HIV-1) activity. While unmodified d(TGGGAG) (31) had no anti-HIV-1 activity, compound 23 with a 3,4-di(benzyloxy)benzyl (DBB) group at the 5'-end potently inhibited the HIV-1IIIB-induced cytopathicity of MT-4 cells in vitro (IC50 = 0.37 microM) without cytotoxicity up to 40 microM. A thermal denaturation study on the 5'-end-substituted 6-mers by means of the circular dichroism (CD) spectra demonstrated that the aromatic substituent attached at the 5'-end of the 6-mer strongly enhanced the formation of a parallel helical structure consisting of four strands (quadruplex). On the contrary, compound 36, in which one of the guanosines of 23 was replaced by a thymidine, did not form a quadruplex, thus exhibiting no anti-HIV-1 activity. Moreover, both compound 15, with a tert-butyldiphenylsilyl group solely at its 3'-end, and compound 21, with a relatively small substituent, a benzyl group, at the 5'-end, formed quadruplexes but had no anti-HIV-1 activity. These findings led us to the conclusion that both the quadruplex structure and the aromatic substituent with adequate size at the 5'-end are crucial for the interaction of the 5'-end-substituted 6-mers with the V3 loop as well as the CD4 binding site on viral gp120, resulting in anti-HIV-1 activity.
Hotoda
H
H
Exploratory Chemistry Research Laboratories, Biological Research Laboratories, Sankyo Company, Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. hotoda@shina.sankyo.co.jp
Koizumi
M
M
Koga
R
R
Kaneko
M
M
Momota
K
K
Ohmine
T
T
Furukawa
H
H
Agatsuma
T
T
Nishigaki
T
T
Sone
J
J
Tsutsumi
S
S
Kosaka
T
T
Abe
K
K
Kimura
S
S
Shimada
K
K
D019380:Anti-HIV Agents / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002461:Cell Line, Transformed; D002942:Circular Dichroism; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008968:Molecular Conformation; D009838:Oligodeoxyribonucleotides / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D009838:Oligodeoxyribonucleotides; D012996:Solutions