Inhibition of HIV-1 RNase H Activity by Nucleotide Dimers and Monomers

Abstract

Nucleotide dimers and monomers were shown to inhibit human immunodeficiency virus type 1 (HIV) RNase H activity. Several effective inhibitors were identified and placed into three general groups based on biochemical 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 cellular RNases H or HIV reverse transcriptase (RT). The second group (group B) inhibited the RNase H activity of several retroviruses as well as the reverse transcriptase function of HIV RT. The third group (group C) inhibited RNases H from retroviral and cellular sources but did not inhibit HIV RT. Kinetic analyses of HIV RNase H inhibition were conducted and all three types of inhibitors exhibited a competitive mode of inhibition with regard to substrate. The small nucleotides described here represent the most potent (Ki values from 0.57 to 16 μM) and selective inhibitors of HIV RNase H reported to date. Further structure - function analyses of these molecules may lead to the discovery of unique, potent antiretroviral therapeutics.

HIV-1 RNase H: Recent Progress in an Exciting, yet Little Explored, Drug Target

“…The nucleotide dimer diguanosine, rGrG, was also shown to stop RNase H reaction with an IC 50 value of 15 µM while it was inactive on cellular RNase Hs [60]. Substitution of its 3'-5'-phosphodiester linker with a 2'-5'-formacetal led to compound (5), (Fig.…”

“…Substitution of its 3'-5'-phosphodiester linker with a 2'-5'-formacetal led to compound (5), (Fig. 2), that showed a little increase in potency against the RT-associated RNase H (IC 50 value of 5 µM), no effect on its RDDP and a modest inhibitory potency on bacterial E. coli RNase H (IC 50 value of 50 µM) [60].…”

Recent Progress in the Design of Small Molecule Inhibitors of HIV RNase H

“…Diguanosine, rGrG, was the most potent unmodified dinucleotide inhibitor of HIV-RH (IC50 = 15 µM) and did not inhibit either E. coli RH or RH activity in HeLa cell nuclear extract [70]. The substitution of the 3'-5'-phosphodiester linker with a 2'-5'-formacetal slightly increased potency against HIV-RH (IC50 = 5 µM).…”

“…The substitution of the 3'-5'-phosphodiester linker with a 2'-5'-formacetal slightly increased potency against HIV-RH (IC50 = 5 µM). 15 showed measurable inhibition of E. coli and HeLa RH activities, albeit with approximately 10-fold lower inhibitory potency, and no inhibition of HIV-RT activity (IC50 > 100 µM) [70].…”

“…Nucleotide dimers have been described as specific HIV-RH and influenza endonuclease inhibitors [70,71]. Diguanosine, rGrG, was the most potent unmodified dinucleotide inhibitor of HIV-RH (IC50 = 15 µM) and did not inhibit either E. coli RH or RH activity in HeLa cell nuclear extract [70].…”