Calanolide A, recently discovered in extracts from the tropical rainforest tree, Calophyllum lanigerum, is a novel inhibitor of the human immunodeficiency virus (HIV) type 1. The compound is essentially inactive against strains of the less common HIV type 2. The present study focused on the further characterization of the selective
antiviral activity and mechanism of action of
calanolide A. The compound inhibited a wide variety of laboratory strains of HIV type 1, with EC50 values ranging from 0.10 to 0.17 microM. The compound similarly inhibited promonocytotropic and lymphocytotropic isolates from patients in various stages of HIV disease, as well as
drug-resistant strains. Viral life-cycle studies indicated that
calanolide A acted early in the
infection process, similar to the known
HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In
enzyme inhibition assays,
calanolide A potently and selectively inhibited recombinant HIV type 1 RT but not cellular
DNA polymerases or HIV type 2 RT within the concentration range tested. Serial passage of the virus in host cells exposed to increasing concentrations of
calanolide A yielded a
calanolide A resistant virus strain. RT from the resistant virus was not inhibited by
calanolide A but retained sensitivity to other nonnucleoside as well as
nucleoside RT inhibitors, including
3'-azido-2',3'-dideoxythymidine triphosphate and
nevirapine. The study substantially supports the conclusion that
calanolide A represents a novel subclass of nonnucleoside RT inhibitor which merits consideration for
anti-HIV drug development.