Structure�Activity of Inhibition of HIV-1 Integrase and Virus Replication by G-quartet Oligonucleotides

Jing, Naijie; Marchand, Christophe; Guan, Yongli; Liu, Jie; Pallansch, Luke; Lackman-Smith, Carol; De Clercq, Erik; Pommier, Yves
August 2001
DNA & Cell Biology;Aug2001, Vol. 20 Issue 8, p499
Academic Journal
As novel anti-HIV agents, the G-tetrad-forming oligonucleotides have been explored for their structure�activity relations with regard to inhibition of integrase (IN) (N. Jing, Expert Opin. Investig. Drugs (2000) 9, 1777�1785). We have now developed two families of G-quartet oligonucleotides: T40217�T40222, with potential formation of a tail-to-tail G-quartet dimer, and T40224�T40227, with phosphorothioate (PT) linkages in the guanine loops. The results obtained from biophysical measurements and the assays of the inhibition of HIV-1 IN and virus replication demonstrated that an increase in the length of the G-quartet structure from a monomer (15�) to a tail-to-tail dimer (47�) does not distinctly disrupt the inhibition of HIV-1 IN activity or the inhibition of HIV-1 replication in cell cultures. G-quartet oligonucleotides were observed to induce molecular aggregation of HIV-1 IN and interrupt the binding of viral DNA to HIV-1 IN. Also, PT substitutions did not confer any advantages compared with the regular phosphodiesters for the inhibition of HIV-1 replication by intramolecular G-quartets. The G-quartet motif is the primary requirement for the remarkable nuclease resistance and pronounced biological efficacy of these oligonucleotides.


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