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J Biol Chem, Vol. 275, Issue 5, 3421-3430, February 4, 2000

Stability-Activity Relationships of a Family of G-tetrad Forming Oligonucleotides as Potent HIV Inhibitors
A BASIS FOR ANTI-HIV DRUG DESIGN^*

Naijie Jing^§, Erik De Clercq^¶, Robert F. Rando, Luke Pallansch^**, Carol Lackman-Smith^**, Sandy Lee, and Michael E. Hogan

From the  Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, the ^¶ Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium, the  Biochem Pharma, Laval, Québec H7V 4A7, Canada, and the ^** Southern Research Institute, Frederick, Maryland 21701

Recently, we have demonstrated that T30695, a G-tetrad-forming oligonucleotide, is a potent inhibitor of human immunodeficiency virus, type I (HIV-1) integrase and the K⁺-induced loop folding of T30695 plays a key role in the inhibition of HIV-1 integrase (Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). Here we have modified T30695 by introducing a hydrophobic bulky group, propynyl dU, or a positively charged group, 5-amino dU, into the bases of T residues of the loops, and by substitution of the T-G loops by T-T loops. Physical measurements have demonstrated that the substitution of propynyl dU or 5-amino dU for T in the T residues of the loops did not alter the structure of T30695, and these derivatives also formed an intramolecular G-quartet structure, which is an essential requirement for anti-HIV activity. Measured IC₅₀ and EC₅₀ values show that these substitutions did not induce an apparent decrease in the ability to inhibit HIV-1 integrase activity and in the inhibition of HIV-1 replication in cell culture. However, the substitution of T-T loops for T-G loops induced a substantial decrease in both thermal stability and anti-HIV activity. The data analysis of T30695 and the 21 derivatives shows a significant, functional correlation between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 integrase activity and between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 replication, as assessed with the virus strains HIV-1 RF, IIIB, and MN in cell culture. This relationship between thermostability and activity provides a basis for improving the efficacy of these compounds to inhibit HIV-1 integrase activity and HIV-1 replication in cell culture.

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