INHIBITION OF HIV-1 RNASE-H ACTIVITY BY NUCLEOTIDE DIMERS AND MONOMERS

Nucleotide dimers and monomers were shown to inhibit human immunodefic iency virus type 1 (HIV) RNase H activity. Several effective inhibitor s were identified and placed into three general groups based on bioche mical characterization of their inhibition. The first group (group A) inhibited HIV RNase H and the closely related feline immunodeficiency virus (FIV) RNase H, but did not inhibit less related retroviral or ce llular RNases H or HIV reverse transcriptase (RT). The second group (g roup B) inhibited the RNase H activity of several retroviruses as well as the reverse transcriptase function of HIV RT. The third group (gro up C) inhibited RNases H from retroviral and cellular sources but did not inhibit HIV RT. Kinetic analyses of HIV RNase H inhibition were co nducted and all three types of inhibitors exhibited a competitive mode of inhibition with regard to substrate. The small nucleotides describ ed here represent the most potent (Ki values from 0.57 to 16 mu M) and selective inhibitors of HIV RNase H reported to date. Further structu re - function analyses of these molecules may lead to the discovery of unique, potent antiretroviral therapeutics.