A novel mechanism for inhibition of HIV-1 reverse transcriptase

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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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 IC50 of 90nM for inhibition of polymerase chain extension, a Kd of 40nM for inhibition of DNA-RT binding, and an IC50 of 25-100nM 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 T4 DNA polymerase, T7 DNA polymerase, or the Klenow fragment at concentrations up to 200nM. 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.

Original languageEnglish (US)
Pages (from-to)443-458
Number of pages16
JournalBioorganic Chemistry
Issue number6
StatePublished - Dec 2002

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry


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