One of the three key
enzymes encoded by the pol gene of HIV is a M(r) 32 000
protein called
HIV integrase. This viral
enzyme is involved in the integration of HIV
DNA into host chromosomal
DNA. There appears to be no functional equivalent of the
enzyme in human cells. The biochemical mechanism of integration of HIV
DNA into the host cell genome involves 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. Thus, new knowledge on inhibitors of this
enzyme is of critical importance in the
anti-HIV drug discovery area. The focus of this review will be on several classes of compounds, including
nucleotides, dinucleotides,
oligonucleotides and miscellaneous small molecules such as heterocyclic systems, natural products, diketo
acids and
sulfones, that have been discovered as inhibitors of
HIV integrase. Special emphasis in the review will be placed on discoveries from my laboratory on
HIV integrase inhibitors that are non-natural, nuclease-resistant dinucleotides. Comments on future directions and the prospects for developing
integrase inhibitors as therapeutic
antiviral agents are discussed.