Unique anti-human immunodeficiency virus activities of the nonnucleoside reverse transcriptase inhibitors calanolide A, costatolide, and dihydrocostatolide

(+)-Calanolide A (NSC 650886) has previously been reported to be a unique a nd specific nonnucleoside inhibitor of the reverse transcriptase (RT) of hu man immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. P harmacol. Exp. Ther., 279:645-651, 1996). Two isomers of calanolide A, (-)- calanolide B (NSC 661122; costatolide) and (-)-dihydrocalanolide B (NSC 661 123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic proper ties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NN RTIs). The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT. Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT. In addition, enzymat ic inhibition assays have demonstrated that the compounds inhibit RT throug h a mechanism that affects both the K-m for dTTP and the V-max, i.e., mixed -type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, incl uding those representative of the various HIV-1 clade strains, syncytium-in ducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropi c isolates. Similar to calanolide A, decreased activities of the two isomer s were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a sma ller loss of activity against many of these NNRTI-resistant isolates. Compa rison of cross-resistance data obtained with a panel of NNRTI-resistant vir us strains suggests that each of the three stereoisomers may interact diffe rently with the RT, despite their high degree of structural similarity. Sel ection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid ch anges in the RT. Similarly, a variety of resistant virus strains with diffe rent amino acid changes were selected in cell culture when the calanolide a nalogs were used in combination with other active anti-HIV agents, includin g nucleoside and nonnucleoside RT and protease inhibitors. In assays with c ombinations of anti-HIV agents, costatolide exhibited synergy with these an ti-HIV agents. The calanolide isomers represent a novel and distinct subgro up of the NNRTI family, and these data suggest that a compound of the calan olide A series, such as costatolide, should be evaluated further for therap eutic use in combination with other anti-HIV agents.