Buckheit R W, White E L, Fliakas-Boltz V, Russell J, Stup T L, Kinjerski T L, Osterling M C, Weigand A, Bader J P
Infectious Disease Research Department, Serquest/Southern Research Institute, Frederick, Maryland 21701, USA.
Antimicrob Agents Chemother. 1999 Aug;43(8):1827-34. doi: 10.1128/AAC.43.8.1827.
(+)-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 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, 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.
(+)-卡拉诺利德A（NSC 650886）先前已被报道是1型人类免疫缺陷病毒（HIV-1）逆转录酶（RT）独特且特异的非核苷抑制剂（M. J. 柯伦斯等人，《药理学与实验治疗学杂志》，279:645 - 651，1996年）。卡拉诺利德A的两种异构体，(-)-卡拉诺利德B（NSC 661122；考斯塔托利德）和(-)-二氢卡拉诺利德B（NSC 661123；二氢考斯塔托利德），具有与卡拉诺利德A相似的抗病毒特性。这三种化合物中的每一种都具有非核苷逆转录酶抑制剂（NNRTIs）药理学类别所具有的表型特性。然而，卡拉诺利德类似物对携带因RT中氨基酸变化Y181C产生的最普遍NNRTI耐药性的耐药病毒表现出10倍增强的抗病毒活性。对于具有Y181C变化以及对齐多夫定产生耐药性的突变的RT，观察到活性进一步增强。此外，酶抑制试验表明，这些化合物通过影响dTTP的K(m)和V(max)的机制抑制RT，即混合型抑制。在新鲜的人类细胞中，考斯塔托利德和二氢考斯塔托利德是低传代临床病毒株的高效抑制剂，包括代表各种HIV-1进化枝菌株、合胞体诱导型和非合胞体诱导型分离株以及T嗜性和单核细胞嗜性分离株的病毒株。与卡拉诺利德A类似，在RT中L100、K103、T139和Y188残基处有氨基酸变化的病毒和RT中观察到这两种异构体的活性降低，尽管考斯塔托利德对许多这些NNRTI耐药分离株的活性损失较小。用一组NNRTI耐药病毒株获得的交叉耐药数据比较表明，尽管这三种立体异构体具有高度的结构相似性，但它们与RT的相互作用可能不同。在多种细胞系中选择对这三种化合物中的每一种耐药的病毒，得到了RT中具有T139I、L100I、Y188H或L187F氨基酸变化的病毒。同样，当卡拉诺利德类似物与其他活性抗HIV药物（包括核苷和非核苷RT及蛋白酶抑制剂）联合使用时，在细胞培养中选择了具有不同氨基酸变化的多种耐药病毒株。在抗HIV药物组合试验中，考斯塔托利德与这些抗HIV药物表现出协同作用。卡拉诺利德异构体代表了NNRTI家族中一个新的独特亚组，这些数据表明，卡拉诺利德A系列的化合物，如考斯塔托利德，应进一步评估与其他抗HIV药物联合用于治疗的用途。
