A novel mechanism for inhibition of HIV-1 reverse transcriptase.

Abstract

The human immunodeficiency virus (HIV) epidemic is an important medical problem. Although combination drug regimens have produced dramatic decreases in viral load, current therapies do not provide a cure for HIV infection. We have used structure-based design and combinatorial medicinal chemistry to identify potent and selective HIV-1 reverse transcriptase (RT) inhibitors that may work by a mechanism distinct from that of current HIV drugs. The most potent of these compounds (compound 4, 2-naphthalenesulfonic acid, 4-hydroxy-7-[[[[5-hydroxy-6-[(4-cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]carbonyl]amino]-3-[(4-cinnamylphenyl)azo], disodium salt) has an IC(50) of 90 nM for inhibition of polymerase chain extension, a K(d) of 40 nM for inhibition of DNA-RT binding, and an IC(50) of 25-100 nM for inhibition of RNaseH cleavage. The parent compound (1) was as effective against 10 nucleoside and non-nucleoside resistant HIV-1 RT mutants as it was against the wild-type enzyme. Compound 4 inhibited HIV-1 RT and murine leukemia virus (MLV) RT, but it did not inhibit T(4) DNA polymerase, T(7) DNA polymerase, or the Klenow fragment at concentrations up to 200 nM. Finally, compound 4 protected cells from HIV-1 infection at a concentration more than 40 times lower than the concentration at which it caused cellular toxicity.

• Authors: A Geoffrey Skillman, Karl W Maurer, Diana C Roe, Margaret J Stauber, Dolan Eargle, Todd J A Ewing, Angelika Muscate, Elisabeth Davioud-Charvet, Maxine V Medaglia, Robert J Fisher, Edward Arnold, Hong Qiang Gao, Robert Buckheit, Paul L Boyer, Stephen H Hughes, Irwin D Kuntz, George L Kenyon
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 30 Issue 6 Pg. 443-58 (Dec 2002) ISSN: 0045-2068 [Print] United States
• PMID: 12642128 (Publication Type: Journal Article)

Chemical References

• Reverse Transcriptase Inhibitors
• HIV Reverse Transcriptase
• Ribonuclease H

Topics

• Algorithms
• Binding Sites
• HIV Reverse Transcriptase (chemistry, metabolism)
• HIV-1 (enzymology)
• Humans
• Kinetics
• Reverse Transcriptase Inhibitors (chemistry, pharmacology)
• Ribonuclease H (metabolism)