Technology Bundle ID
NCI-E-081-2011

Anti-Viral Compounds that Inhibit HIV Activity

Applications
Lead Inventors
John Beutler (NCI)
Co-Inventors
Craig Thomas (NCI)
Stuart LeGrice (NCI)
Development Status
Discovery (Lead Identification)
ICs

Several novel tropolone derivatives have been identified that inhibit HIV-1 RNase H function and have potential for anti-viral activity due to reduced cellular toxicity.  Inhibiting RNase H function is a potential treatment for many viral infections, since RNase H function is essential for viral replication for many pathogenic retroviruses such as HIV-1 and HIV-2.  Although many hydroxytropolone compounds are potent RNase H inhibitors biding at the enzymatic active site, they are limited as therapeutic candidates by their toxicity in mammalian cells.  The toxicity thought to be a result of inhibition of multiple essential mammalian metalloenzymes.  We reasoned that the potential beneficial application of tropolone RNase H inhibition might be of therapeutic use if the toxic effects in mammalian cell were eliminated.  By selectively adding steric bulk to add new drug-enzyme contacts for the RNase H active site, a number of novel compounds, that have initially demonstrated reduced cytotoxicity, have been produced.  Importantly, these novel compounds appear to retain antiviral activity essential for use as therapeutics.

Commercial Applications
  • As an HIV-1 therapeutic
Competitive Advantages
  • Potentially reduced toxicity
  • Availability of x-ray crystallographic information to guide analog design

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