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.