Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity

Sanjeev Kumar V. Vernekar, Jing Tang, Bulan Wu, Andrew D. Huber, Mary C. Casey, Nataliya Myshakina, Daniel J. Wilson, Jayakanth Kankanala, Karen A. Kirby, Michael A. Parniak, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 languageEnglish (US)
Pages (from-to)5045-5056
Number of pages12
JournalJournal of medicinal chemistry
Volume60
Issue number12
DOIs
StatePublished - Jun 22 2017

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health (AI100890 to S.G.S., M.A.P., and Z.W.).

Publisher Copyright:
© 2017 American Chemical Society.

Fingerprint

Dive into the research topics of 'Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity'. Together they form a unique fingerprint.

Cite this