Carl Jones and Dr. Matt Peterson, Department of Chemistry and Biochemistry

The ultimate goal of this project is to synthesize a library of compounds designed specifically to inhibit HIV integrase. HIV integrase is the enzyme that incorporates viral DNA into host DNA. Currently, there are no FDA approved inhibitors of HIV integrase. This makes it an attractive target for therapeutic intervention because it is the only one of the three essential retroviral enzymes for which antiretroviral drugs have not been synthesized.

To identify compounds that might bind HIV integrase, we have performed ligand binding studies using the state-of-the-art ligand docking module in SYBYL6.9, Tripos, Inc. This software has been shown to be between fifty and seventy five percent accurate when comparing known crystal structures of ligand-protein complexes to the software’s theoretical calculations. We loaded the structure of adenosine onto SYBYL, along with one crystal structure of HIV integrase. The substituents at the 3’, 5’, and 6 positions of adenosine were varied to find the combination with the greatest binding affinity for the enzyme. Of over 49,000 compounds screened, we have chosen sixty compounds which were indicated by modeling to hold great potential as ligands for HIV integrase.

In the past year, we have made significant progress in the synthesis of the desired compounds. I synthesized large quantities of starting materials that will be used for the entire series of reactions. Within the past four months, the first few of the desired compounds have been synthesized, characterized, purified, and will soon be sent for biological testing.

Several difficulties arose in the syntheses of the desired compounds. The most baffling of which was an azide displacement of chlorine at the 5′ position. The method normally used for this reaction is to add sodium azide and the chlorine containing compound to a solution and heat the mixture. This method, however, only gave 30% of the desired product, which was unacceptable at such a late stage in the reaction scheme. After many failed attempts, the problem was finally solved using a technique that cannot be disclosed until published in a chemistry journal. The new technique gives nearly 100% yield of the desired product and prevents the formation of cyclonucleosides, which are a pervasive problem in nucleoside chemistry.

Several more compounds must still be synthesized, and results from biological testing of the first series of compounds will allow us to focus more closely on structures that show the most biological activity. We can then modify the compound slightly to improve binding to the enzyme.