The viral
enzyme,
HIV integrase (MW 32 kDa), is one of the three key
enzymes of the pol gene of HIV.
HIV integrase is involved in the integration of HIV
DNA into host chromosomal
DNA. There is apparently no functional equivalent of this
enzyme in human cells. Integration of HIV
DNA into the host cell genome apparently occurs by a carefully defined sequence of
DNA tailoring (3'-processing) and coupling (joining or integration) reactions. In spite of some effort in this area targeted at the discovery of therapeutically useful inhibitors of this viral
enzyme, there are no drugs for HIV/
AIDS in clinical use where the mechanism of action is inhibition of
HIV integrase. It is clear that new knowledge on inhibitors of this
enzyme is of critical importance in the
anti-HIV drug discovery area. This review focuses on the major classes of compounds that have been discovered as inhibitors of
HIV integrase. Some of these compounds are non-specific inhibitors of the
enzyme while evidence suggests that others may possess some specificity. The various classes include
nucleotides,
oligonucleotides, dinucleotides, and miscellaneous small molecules including heterocyclic systems, natural products, diketo
acids and
sulfones. A major focus of the review is on discoveries from my laboratory in the area of non-natural, nuclease-resistant dinucleotide inhibitors of
HIV integrase.