title: Structure-activity of tetrad-forming oligonucleotides as a potent anti-HIV therapeutic drug.
abstract: Recently, we have described the design and characterization of oligonucleotides containing only G and T bases, i.e. T30695 and T30177, that are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in culture (Jing, N., Rando, R. F., Pommier, Y., and Hogan, M. E. (1997) Biochemistry 36, 12498-12505). To understand that observation and to rationalize the generally high thermal stability of oligonucleotide folding for these compounds, we have used NMR methods, coupled to molecular modeling, to obtain a high resolution structure model for T30695, which is the most potent of the integrase inhibitors that have been identified thus far. Modeling and NMR data obtained in the presence of Li+ ions show that T30695 assumes an intramolecular fold with a distorted G-octet core and a set of three open, partially disordered loops. This is referred to as Li+-form structure. The NMR-based model suggests that, upon coordination with three K+ equivalents, the central G-octet becomes more regular and that the loop domains become orderly and compact. This is referred to as K+-form structure. Based upon the assay of inhibition of HIV-1 integrase, T30695 demonstrated a strong inhibition of HIV-1 integrase activity as the K+-form structure, but a poor inhibition of HIV-1 integrase activity as the Li+-form structure. The structure/activity analysis suggests that the K+-induced conformation transition of the tetrad-forming oligonucleotides, such as T30695 and T30177, plays a key role in inhibition of HIV-1 integrase activity.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA. njing@bcm.tmc.edu
authors.forename: N
authors.initials: N
authors.lastname: Jing
authors.forename: M E
authors.initials: ME
authors.lastname: Hogan
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D052157:Aptamers, Nucleotide; D019427:HIV Integrase / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D052157:Aptamers, Nucleotide; D019428:HIV Integrase Inhibitors; D009841:Oligonucleotides; C116759:T 30695; C081676:thrombin aptamer; C098172:T 30177; D019427:HIV Integrase; D011188:Potassium