Anti-Viral Compounds that Inhibit HIV Activity


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.



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


Development Stage:
Discovery (Lead Identification)

Related Invention(s):
E-183-2009


Inventors:

John Beutler (NCI)  ➽ more inventions...

Stuart LeGrice (NCI)  ➽ more inventions...

Craig Thomas (NCI)  ➽ more inventions...


Intellectual Property:
US Application No. 8993768
Foreign Filed Application No. WO2012154904

Publications:
Chung S, et al. Synthesis, activity and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H. PMID 21568335

Collaboration Opportunity:

Licensing and research collaboration


Licensing Contact:
John Hewes, Ph.D.
Email: John.Hewes@nih.gov
Phone: 240-276-5515

OTT Reference No: E-081-2011
Updated: Apr 20, 2018