Xu Z Q, Flavin M T, Jenta T R
Sarawak MediChem Pharmaceuticals Inc, Lemont, IL 60439, USA.
Curr Opin Drug Discov Devel. 2000 Mar;3(2):155-66.
Both naturally occurring and semi-synthetic calanolide compounds are potent anti-human immunodeficiency virus (HIV) agents. In fresh human cells, they are highly effective inhibitors against low passage clinical virus strains, including those representative of the various HIV-1 clade strains (A through F), syncytium-inducing (SI) and non-syncytium-inducing (NSI) isolates, and T-tropic and monocyte-tropic isolates. These compounds also exhibit an enhanced antiviral activity against one of the most prevalent non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant viruses that is engendered by the Y181C amino acid change in reverse transcriptase (RT). Further enhancement of activity is observed with RTs that possess the Y181C change together with AZT-resistant mutations. Moreover, when challenged with viruses containing Y181C and K103N dual mutations, calanolide compounds remain active. These dual mutations are highly resistant to all approved NNRTIs (eg, delavirdine, nevirapine and efavirenz). In cell culture assays, calanolide compounds, especially (+)-calanolide A, select primarily resistant viruses possessing the T139I amino acid change. This mutation appears to be unique to calanolides since it remains susceptible to other NNRTIs. Synergistic effects are observed in both cultured cells and animal models when calanolides are used in combination with other anti-HIV agents. Enzymatic analyses indicate that calanolides inhibit HIV-1 RT through a mechanism that affects both the Km for normal substrate dTTP and the Vmax, resulting in a mixed-type inhibition, which is different from that of other known NNRTIs. Two possible binding modes/sites at the HIV-1 RT enzyme have been suggested for (+)-calanolide A. Taken together, the calanolide compounds represent a novel and distinct subgroup of the NNRTI family and inclusion of a calanolide in a combination therapy may be clinically beneficial. Of particular interest is the use of calanolide in the treatment of patients who have failed other NNRTI therapy and developed the Y181C mutation or the Y181C/K103N dual mutations. Currently, (+)-calanolide A, the most potent in the series of calanolide compounds, is undergoing clinical investigation for safety and efficacy in HIV-infected individuals.
天然存在的和半合成的可乐那韦化合物都是有效的抗人类免疫缺陷病毒（HIV）药物。在新鲜的人类细胞中，它们是针对低传代临床病毒株的高效抑制剂，包括代表各种HIV-1进化枝毒株（A至F）、合胞体诱导（SI）和非合胞体诱导（NSI）分离株以及T嗜性和单核细胞嗜性分离株的病毒株。这些化合物还对由逆转录酶（RT）中的Y181C氨基酸变化产生的最普遍的非核苷类逆转录酶抑制剂（NNRTI）抗性病毒之一表现出增强的抗病毒活性。对于具有Y181C变化以及AZT抗性突变的RT，观察到活性进一步增强。此外，当用含有Y181C和K103N双重突变的病毒进行攻击时，可乐那韦化合物仍然具有活性。这些双重突变对所有已批准的NNRTIs（例如地拉韦啶、奈韦拉平和依非韦伦）具有高度抗性。在细胞培养试验中，可乐那韦化合物，尤其是（+）-可乐那韦A，主要选择具有T139I氨基酸变化的抗性病毒。这种突变似乎是可乐那韦所特有的，因为它对其他NNRTIs仍然敏感。当可乐那韦与其他抗HIV药物联合使用时，在培养细胞和动物模型中均观察到协同效应。酶分析表明，可乐那韦通过一种影响正常底物dTTP的Km和Vmax的机制抑制HIV-1 RT，导致混合型抑制，这与其他已知的NNRTIs不同。已提出（+）-可乐那韦A在HIV-1 RT酶上有两种可能的结合模式/位点。综上所述，可乐那韦化合物代表了NNRTI家族中一个新颖且独特的亚组，在联合治疗中加入可乐那韦可能具有临床益处。特别令人感兴趣的是可乐那韦在治疗其他NNRTI治疗失败并发生Y181C突变或Y181C/K103N双重突变的患者中的应用。目前，可乐那韦化合物系列中最有效的（+）-可乐那韦A正在对HIV感染个体进行安全性和有效性的临床研究。
