Mechanism of inhibition of HIV-1 integrase by G-tetrad-forming oligonucleotides in vitro

The G-tetrad-forming oligonucleotides T30177 and T30695 have been identifie d as potent inhibitors of human immunodeficiency virus type 1 integrase (HI V-1 IN) activity (Rando, R. F., Ojwang, J., Elbaggari, A., Reyes, G. R., Ti nder, R., McGrath, M. S., and Hogan, M. E. (1995) J. Biol. Chem. 270, 1754- 1760; Mazumder, A., Neamati, N., Ojwang, J. O., Sunder, S., Rando, R. F., a nd Pommier, Y. (1996) Biochemistry 35, 13762-13771; Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). To understand the inhibition o f HIV-1 IN activity by the G-quartet inhibitors, we have designed the oligo nucleotides T40215 and T40216, composed of three and four G-quartets with s tem lengths of 19 and 24 Angstrom, respectively. The fact that increasing t he G-quartet stem length from 15 to 24 Angstrom kept inhibition of HIV-1 IN activity unchanged suggests that the binding interaction occurs between a GTGT loop domain of the G-quartet inhibitors and a catalytic site of HIV-1 ZN, referred to as a face-to-face interaction. Docking the NMR structure of T30695 (Jing and Hogan (1998)) into the x-ray structure of the core domain of HIV-1 IN, HIV-1 IN-(51-209) (Maignan, S., Guilloteau, J.-P., Qing, Z.-L ., Clement-Mella, C., and Mikol, V. (1998) J. Mel. Biol. 282, 359-368), was performed using the GRAMM program. The statistical distributions of hydrog en bonding between HIV-1 IN and T30695 were obtained from the analyses of 1 000 random docking structures. The docking results show a high probability of interaction between the GTGT loop residues of the G-quartet inhibitors a nd the catalytic site of HIV-1 IN, in agreement with the experimental obser vation.