Biological and biochemical anti-human immunodeficiency virus activity of UC 38, a new non-nucleoside reverse transcriptase inhibitor.
UC 38, a simple analog of oxathiin carboxanilide, UC 84, lacking the oxathiin ring, was found to be a potent inhibitor of human immunodeficiency virus (HIV)-1-induced cell killing and HIV replication in a variety of human cell lines, as well as in human peripheral blood lymphocytes and macrophages. UC 38 was active against a wide range of biologically diverse laboratory and clinical strains of HIV-1. However, UC 38 was inactive against HIV-2 and both nevirapine- and pyridinone-resistant strains of HIV-1. UC 38 selectively inhibited HIV-1 reverse transcriptase (RT), but not HIV-2 RT. Combination of UC 38 with 3'-azido-3'-deoxythymidine synergistically inhibited HIV-induced cell killing. An HIV-1 isolate resistant to UC 38 was selected in cell culture, and the mutations in the RT nucleotide sequences were determined. Comparison with the wild-type RT sequence revealed an amino acid change at position 181 (Tyr to Cys). The UC 38-resistant virus was found to be cross-resistant to a variety of structurally diverse non-nucleoside RT inhibitors. UC 38 was susceptible to rapid degradation in vitro and in vivo; yet, nontoxic in vivo concentrations of UC 38 many-fold in excess of the in vitro effective concentrations could be achieved and maintained after s.c. or p.o. administration in hamsters. These results establish UC 38 as a new chemotype within the general class of HIV-1-specific RT inhibitors. The favorable physical characteristics, lack of toxicity, potency and bioavailability of UC 38 may make it a candidate for combination chemotherapy of acquired immune deficiency syndrome.
McMahon
J B
JB
Laboratory of Drug Discovery Research and Development, National Cancer Institute, Frederick, Maryland, USA.
Buckheit
R W
RW
Gulakowski
R J
RJ
Currens
M J
MJ
Vistica
D T
DT
Shoemaker
R H
RH
Stinson
S F
SF
Russell
J D
JD
Bader
J P
JP
Narayanan
V L
VL
Schultz
R J
RJ
Brouwer
W G
WG
Felauer
E E
EE
Boyd
M R
MR
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001565:Benzoates / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002261:Carboxin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial; D004355:Drug Stability; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D001565:Benzoates; D004279:DNA, Viral; C070134:NSC 615985; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C083308:NSC 629243; D015215:Zidovudine; D002261:Carboxin; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase