Anti-HIV-1 activity of calanolides used in combination with other mechanistically diverse inhibitors of HIV-1 replication.
The natural product (+)-calanolide A, a unique non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication, is currently being evaluated in clinical trials in the USA. (+)-Calanolide A, the congeners costatolide and dihydrocostatolide, and (+)-12-oxo(+)-calanolide A, were evaluated in combination with a variety of mechanically diverse inhibitors of HIV replication to define the efficacy and cellular toxicity of potential clinical drug combinations. These assays should be useful in prioritizing the use of different combination drug strategies in a clinical setting. The calanolides exhibited synergistic antiviral interactions with other nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Additive interactions were also observed when the calanolides were used with representative compounds from each of these classes of inhibitors. No evidence of either combination toxicity or antagonistic antiviral activity was detected with any of the tested compounds. The combination antiviral efficacy of three-drug combinations involving the calanolides, and the efficacy of two- and three-drug combinations using a (+)-calanolide A-resistant challenge virus (bearing the T139I amino acid change in the reverse transcriptase), was also evaluated in vitro. These assays suggest that the best combination of agents based on in vitro anti-HIV assay results would include the calanolides in combination with lamivudine and nelfinavir, since this was the only three-drug combination exhibiting a significant level of synergy. Combination assays with the (+)-calanolide A-resistant strain yielded identical results as seen with the wild-type virus, although the concentration of the calanolides had to be increased.
Buckheit
R W
RW
Infectious Disease Research Department, Southern Research Institute, Frederick, MD, USA. buckheit@sri.org
Russell
J D
JD
Xu
Z Q
ZQ
Flavin
M
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003374:Coumarins; D017320:HIV Protease Inhibitors; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; C075959:calanolide A