The pol gene of the human immunodeficiency virus (HIV) encodes three enzymes which are critical for the replication of this virus. Two of these enzymes, HIV reverse transcriptase and HIV protease, have received considerable attention in terms of the development of clinically useful therapeutic agents. The third enzyme of the pol gene, HIV integrase, has received much less attention. Clearly, new information pertaining to inhibitors of this enzyme is of critical importance in the anti-HIV drug discovery area. The long term goals of this project are to contribute to the chemistry and enzymology of compounds that are potent inhibitors of HIV integrase and that have useful therapeutic potential against the cytopathic effect of HIV. This application is focused on a comprehensive study of sequence specific dinucleotides as inhibitors of HIV integrase. The project has seven specific aims.
Specific Aims #1 -#3 are concerned with the design and stereochemical synthesis of three classes of deoxydinucleotides targeted as inhibitors of HIV integrase. The rationale for the design and selection of these compounds for study is based in part on lead compounds with potent HIV integrase inhibitory activity.
Specific Aim #4 involves careful purification of the target compounds and establishment of their structure and stereochemistry by various spectroscopic techniques including multinuclear NMR spectroscopy, circular dichroism (CD) data, and X-ray crystallography.
In Specific Aim #5, stability studies of the internucleotide phosphate bonds as well as the 5'-phosphate monoesters by cellular metabolizing enzymes such as nucleases and phosphatases will be conducted.
In Specific Aim #6, collaborative studies on the inhibition of HIV integrase and on the inhibition of the binding of substrate DNA with integrase will undertaken.
Specific Aim #7 is concerned with comprehensive antiviral studies (including toxicity studies) of the most potent inhibitors of HIV integrase and their selected pro-drug forms. Pharmacokinetic studies of the cellularly most active compound(s) are also planned, as are cellular combination chemotherapeutic studies with selected active compounds. Synergistic inhibition will be examined.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG5-ARRB (01))
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Nair, Vasu; Okello, Maurice (2015) Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of ?-Diketo Acids. Molecules 20:12623-51
Nair, Vasu; Okello, Maurice O; Mangu, Naveen K et al. (2015) A novel molecule with notable activity against multi-drug resistant tuberculosis. Bioorg Med Chem Lett 25:1269-73
Nair, Vasu; Okello, Maurice; Mishra, Sanjay et al. (2014) Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor. Antiviral Res 108:25-9
Bacsa, John; Okello, Maurice; Singh, Pankaj et al. (2013) Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor. Acta Crystallogr C 69:285-8
Okello, Maurice; Nishonov, Malik; Singh, Pankaj et al. (2013) Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor. Org Biomol Chem 11:7852-8
Okello, Maurice; Mishra, Sanjay; Nishonov, Malik et al. (2013) Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations. Bioorg Med Chem Lett 23:4112-6
Okello, Maurice O; Mishra, Sanjay; Nishonov, Malik et al. (2013) A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase metabolism profile. Antiviral Res 98:365-72
Seo, Byung I; Uchil, Vinod R; Okello, Maurice et al. (2011) Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity. ACS Med Chem Lett 2:877-881
Chi, Guochen; Nair, Vasu; Semenova, Elena et al. (2007) A novel diketo phosphonic acid that exhibits specific, strand-transfer inhibition of HIV integrase and anti-HIV activity. Bioorg Med Chem Lett 17:1266-9
Uchil, Vinod; Seo, Byung; Nair, Vasu (2007) A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds. J Org Chem 72:8577-9

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