Anti-Viral Compounds that Inhibit HIV Activity
Ref. No. E-081-2011
AIDS RNase H, tropolone derivative, ribonuclease H, viral
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.
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.
- Potentially reduced toxicity
- Availability of x-ray crystallographic information to guide
U.S. Provisional Application No. 61/484,779
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.
Please submit an information request form at http://techtransfer.cancer.gov
John D. Hewes, Ph.D., (301) 435-3121, email@example.com
Last updated: 05/01/2012
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