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Anti-Viral Compounds that Inhibit HIV Activity

Keywords:  Therapeutic, HIV, AIDS RNase H, tropolone derivative, ribonuclease H, viral replication

Summary: 
The Molecular Targets Laboratory, National Cancer Institute (NCI) is seeks parties interested in collaborative research to co-develop antiviral tropolone derivatives developed by systematic medicinal chemistry on the lead series.

Technology: 
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 Advantages:

• Potentially reduced toxicity
• Availability of x-ray crystallographic information to guide analog design

Development Stage: Early stage, in vitro data available.

Patent Status:  U.S. Provisional Application No. 61/484,779 (05/11/2011)

Publications:   
Chung S, et al. Synthesis, activity and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H. J Med Chem 2011 Jul 14;54(13):4462-4473. 

Budihas SR, et al. Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones. Nucl Acids Res 2005 33 (4):1249-1256.

Contact:
Please submit an information request form at  http://techtransfer.cancer.gov or contact:
John D. Hewes, Ph.D., (301) 435-3121, hewesj@mail.nih.gov.

Last updated: 05/01/2012

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