1. HIV Integrase Therapeutics

2. 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

3. 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

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

5. 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

6. 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

7. 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

8. 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%

9. 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

10. 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,
Gupta, S.P; et al. Design and Development of Integrase Inhibitors as Anti-HIV Agents. Current Medicinal Chemistry, 2003, 10,
Chen, I-Jen.; et al. Structure-Based Inhibitor Design Targeting HIV-1 Integrase. Current Drug Targets, 2002,2,
Marchand, Christophe; et al. Structural Determinants for HIV-1 Integrase Inhibition by -Diketo Acids. J. Biol. Chem., 2002,277,15,
Saliva, Carlos; et al. Rational Design of Novel Diketoacid-Containing Ferrocene Inhibitors of HIV-1 Integrase, Biorg Chem, 2005,33,

11. Questions??