Abstract
Human immunodeficiency virus (HIV) reverse transcriptase (RT)-Associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity. Structure-Activity relationship (SAR) concerning primarily the length and flexibility of the two wings revealed important structural features that dictate the potency and selectivity of RNase H inhibition as well as the observed antiviral activity. Our current medicinal chemistry data also revealed that the RNase H biochemical inhibition largely correlated the antiviral activity.
Original language | English (US) |
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Pages (from-to) | 5045-5056 |
Number of pages | 12 |
Journal | Journal of medicinal chemistry |
Volume | 60 |
Issue number | 12 |
DOIs | |
State | Published - Jun 22 2017 |
Bibliographical note
Publisher Copyright:© 2017 American Chemical Society.