Byung I. Seo

DESIGN AND SYNTHESIS OF SPECIFIC INHIBITORS OF THE 3′-PROCESSING STEP OF HIV-1 INTEGRASE

The novel dinucleotide 5′-phosphate, [(L,D)-pIsodApdC], discovered in our laboratory, is a strong inhibitor of HIV-1 integrase for both the 3′-processing and the strand transfer steps. The rationale used in this molecular design was that residues immediately upstream of the dinucleotide cleavage site in the 3′-processing step might provide critical recognition/binding sites on integrase. The rationale for the second type of inhibitors was based on the elimination products (linear and cyclic dinucleotides) of 3′-processing. However, while the linear dinucleotide 5′-phosphate (pdGpdT) was active, its cyclic counterpart was inactive against both wild-type and mutant HIV integrase.

Biologically-Validated HIV Integrase Inhibitors with Nucleobase Scaffolds: Structure, Synthesis, Chemical Biology, Molecular Modeling, and Antiviral Activity

Integrase, an enzyme of the pol gene of HIV, is a significant viral target for the discovery of anti-HIV agents. In this presentation, we report on the continuation of our work on the discovery of diketo acids, constructed on nucleobase scaffolds, that are inhibitors of HIV integrase. An example of our synthetic approach to inhibitors with purine nucleobase scaffolds is given. Comparison is made between integrase inhibition data arising from compounds with pyrimidine versus purine nucleobase scaffold. Antiviral results are cited.