We present the solution structure of the 93del d(GGGGTGGGAGGAGGGT) aptamer, a potent nanomolar inhibitor of HIV-1 integrase (1). We establish that this 16-nucleotide DNA sequence adopts an unusually stable dimeric quadruplex architecture in K⁺ solution. The structure of each monomer subunit contains two G·G·G·G tetrads and one A·(G·G·G·G) pentad, where all G-stretches are parallel and linked by three single-nucleotide double-chain-reversal loops. Results of NMR and of integrase inhibition assays on loop-modified sequences allowed us to propose a new strategy towards the potential design of improved HIV-1 integrase inhibitors. Finally, we propose a model, based on molecular docking approaches, for positioning the 93del dimeric DNA quadruplex within a basic channel/canyon formed between subunits of a dimer of dimers of HIV-1 integrase (2).

Reference and Footnotes

1. Phan A. T., Kuryavyi V., Ma J. B., Faure, A., Andréola M. L., and Patel D.J. Proc. Natl. Acad. Sci. USA 102, 634-639 (2005).
2. Wang, J. Y., Ling, H., Yang, W., and Craigie, R. EMBO J. 20, 7333-7343 (2001).