HIV Integrase Therapeutics

Brief History 20 years of research has produced 17 FDA approved drugs for AIDS treatment. Previously the drugs target viral enzymes: reverse transcriptase and protease About 11 years ago HIV Integrase Inhibitors were reported Currently two compounds in clinical trials, S-1360 and L-870,810

Inhibitors In order for Inhibitors to efficiently prevent HIV Integrase from functioning they must prevent the following: 3’end processing reaction The removal of GT from the 3’end exposing the CA nucleotide 2. Strand transfer reaction cleavage of DNA and the ligation of the 3’OH ends of viral DNA with the 5’ phosphate end of Target DNA 3. 5’ end joining reaction nucleotides at the 5’ end of viral DNA are removed gaps between the viral and target DNA are repaired. Inhibitors compete with viral DNA to bind to HIV integrase

Function Prevent strand transfer reactions which would otherwise result in the covalent linkage of viral DNA 3’ends to cellular target DNA.

Diketo Acids General Structure: 4-aryl-2-hydroxy-4-oxo-2-butenoic acid Most promising points of Inhibitor Developement Aryl= anything of an aromatic compound

Inhibitor binding Actual binding site of IN not yet understood but it is speculated that the inhibitor recognizes a conformation in the IN active site and binds to it L-708,906 and 5CITEP binds centrally in the active

Inhibitor binding cont… Viral DNA unable to bind to IN Viral DNA is accessible to metabolism by cellular recombination repair enzymes Leads to irreversible blocking of viral replication due to unstable integration

Results of Binding 5CITEP functions more efficiently at lower concentrations than L-708,906 5CITEP active against 3’end processing and strand transfer L-708,906 only active against strand transfer IC50= Inhibition Concentration, Concentration that reduces the Integrase action by 50%

Compounds in Clinical Trial S-1360 comes from Shionogi and Co. in phase two of clinical trials derivative of the 5citep compound, with a triazole instead of a tetrazole Merck Research Labs developed L-870,810 derived from diketo acids as the L-708906

References Johnson, Allison A.; et al. HIV-1 Integrase Inhibitors: A Decade of Research and Two Drugs in Clinical Trial. Current Topics in Medicinal Chemistry 2004,4,1059-1077 Gupta, S.P; et al. Design and Development of Integrase Inhibitors as Anti-HIV Agents. Current Medicinal Chemistry, 2003, 10,1779-1794 Chen, I-Jen.; et al. Structure-Based Inhibitor Design Targeting HIV-1 Integrase. Current Drug Targets, 2002,2,217-234 Marchand, Christophe; et al. Structural Determinants for HIV-1 Integrase Inhibition by -Diketo Acids. J. Biol. Chem., 2002,277,15,12596-12603. Saliva, Carlos; et al. Rational Design of Novel Diketoacid-Containing Ferrocene Inhibitors of HIV-1 Integrase, Biorg Chem, 2005,33,274-284.

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