Correlation of Molecular Conformation and Activity of Reverse Transcriptase Inhibitors

The enzyme reverse transcriptase (RTase) of the human immunodeficiency virus type 1 (HIV-1) is an attractive target for the treatment of AIDS because of its role in the introduction of the viral genetic material into the genome of the host cell. The retroviral RTase displays transcriptase, RNase H, and DNA-polymerase activity in producing DNA from the viral RNA template. Much effort has been devoted to compounds that lack the 3'-hydroxyl substituent of the natural nucleoside because they can act as chain terminators after incorporation into the DNA chain being formed. Although chain termination by AZT has been demonstrated, however, it has not been fully established that it is an essential requirement for activity or that, alternatively, binding of the inhibitor to RTase, at least temporarily blocking the active site, is sufficient for activity.