Structure-activity of inhibition of HIV-1 integrase and virus replication by G-quartet oligonucleotides

As novel anti-HIV agents, the G-tetrad-forming oligonucleotides have been e xplored 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 T40 224-T40227, with phosphorothioate (PT) linkages in the guanine loops. The r esults obtained from biophysical measurements and the assays of the inhibit ion of HIV-1 IN and virus replication demonstrated that an increase in the length of the G-quartet structure from a monomer (15 Angstrom) to a tail-to -tail dimer (47 Angstrom) does not distinctly disrupt the inhibition of HIV -1 IN activity or the inhibition of HIV-1 replication in cell cultures. G-q uartet oligonucleotides were observed to induce molecular aggregation of HI V-1 IN and interrupt the binding of viral DNA to HIV-1 IN. Also, PT substit utions did not confer any advantages compared with the regular phosphodiest ers for the inhibition of HIV-1 replication by intramolecular G-quartets. T he G-quartet motif is the primary requirement for the remarkable nuclease r esistance and pronounced biological efficacy of these oligonucleotides.