Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide

Abstract

(+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. Pharmacol. Exp. Ther., 279:645–651, 1996). Two isomers of calanolide A, (−)-calanolide B (NSC 661122; costatolide) and (−)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs). 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, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the Km for dTTP and theV max, i.e., mixed-type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates. Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity. Selection 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 changes in the RT. Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors. In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents. The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.

Drug discovery from medicinal plants

“…Stevens (Clusiaceae), a Malaysian rainforest tree (Kashman et al, 1992;Yang et al, 2001;. Calanolide A is an anti-HIV drug with a unique and specific mechanism of action as a non-nucleoside reverse transcriptase inhibitor (NNRTI) of type-1 HIV and is effective against AZT-resistant strains of HIV (Currens et al, 1996;Buckheit et al, 1999;Yu et al, 2003). Calanolide A is currently undergoing Phase II clinical trials (Creagh et al, 2001).…”

Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection

“…44 Two isomers of calanolide A, (À)-calanolide B (costatolide) and (À)-dihydrocalanolide B (dihydrocostatolide) possess antiviral properties similar to those of calanolide A. 45 The calanolide analogs exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear one of the most prevalent NNRTI resistance RT mutations (Y181C); in turn, the calanolide analogues lead to the selection of drug-resistant virus strains carrying the T139I, L100I, Y188H or L187F mutations in their RT. 45 The calanolide isomers represent a novel and distinct subgroup of the NNRTI family; they should be further evaluated for their therapeutic potential in combination with other anti-HIV agents.…”

“…45 The calanolide isomers represent a novel and distinct subgroup of the NNRTI family; they should be further evaluated for their therapeutic potential in combination with other anti-HIV agents. 45 …”

Natural Product-Based Anti-HIV Drug Discovery and Development Facilitated by the NCI Developmental Therapeutics Program

“…The most recent analysis includes the following findings and conclusions in a comparative study of the three calanolide isomers. 61 All three calanolides inhibited the laboratory-adapted HIV-1 variants, the clinical viral isolates, inclusive of the diverse clades (A-F), syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. 61 The calanolide isomers were also found to be effective against a wide spectrum of drug-resistant HIV strains isolated from patients' T-cells in tissue culture or HIV-infected T-cell cultures in the presence of the test drug.…”

“…61 All three calanolides inhibited the laboratory-adapted HIV-1 variants, the clinical viral isolates, inclusive of the diverse clades (A-F), syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. 61 The calanolide isomers were also found to be effective against a wide spectrum of drug-resistant HIV strains isolated from patients' T-cells in tissue culture or HIV-infected T-cell cultures in the presence of the test drug. In most cases, their efficacy against the drug-resistant mutants remained the same with little increase in EC 50 , when compared with their corresponding inhibition of the wild-type HIV-1.…”