Small molecule inhibitors of HIV RT Ribonuclease H.
Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established and time of addition studies were consistent with inhibition of RT-mediated HIV replication.
Di Grandi
Martin
M
Wyeth Research, 401 North Middletown Road, Pearl River, NY, United States. digranm@pfizer.com
Olson
Matthew
M
Prashad
Amar S
AS
Bebernitz
Geraldine
G
Luckay
Amara
A
Mullen
Stanley
S
Hu
Yongbo
Y
Krishnamurthy
Girija
G
Pitts
Keith
K
O'Connell
John
J
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D008969:Molecular Sequence Data; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D013859:Thiocarbamates; D014230:Triazoles; D054309:Ribonuclease H, Human Immunodeficiency Virus