A novel mechanism for inhibition of HIV-1 reverse transcriptase.
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.
Skillman
A Geoffrey
AG
Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus Ave, Box 0446, San Francisco, CA 94143-0446, USA.
Maurer
Karl W
KW
Roe
Diana C
DC
Stauber
Margaret J
MJ
Eargle
Dolan
D
Ewing
Todd J A
TJ
Muscate
Angelika
A
Davioud-Charvet
Elisabeth
E
Medaglia
Maxine V
MV
Fisher
Robert J
RJ
Arnold
Edward
E
Gao
Hong Qiang
HQ
Buckheit
Robert
R
Boyer
Paul L
PL
Hughes
Stephen H
SH
Kuntz
Irwin D
ID
Kenyon
George L
GL
D000465:Algorithms; D001665:Binding Sites; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016914:Ribonuclease H / Q000378:metabolism
D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H