4′-ethynyl nucleoside analogs:: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro
4′-ethynyl nucleoside analogs:: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro
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DOI：
10.1128/aac.45.5.1539-1546.2001
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发表时间：
2001-05-01
影响因子：
4.9
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
--
作者：
Kodama, EI;Kohgo, S;Mitsuya, H
设计、合成并鉴定了一系列4 ' -乙炔基（4 ' -E）核苷类似物，其具有抗广谱人类免疫缺陷病毒（HIV）的活性，包括多种实验室HIV-1、HIV-2和主要临床HIV-1分离株。在所检查的这些类似物中，4 ' -E-2 ' -脱氧胞苷（4 ' -E-dC），4 ' -E-2 ' -脱氧腺苷（4 ' -E-dA），4 ' -E-2 ' -脱氧呋喃核糖基-2，6-diamifiopurine和4 ' -E-2 ' -deoxyguanosine对HIV-1复制的阻断作用最强，达50%，体外有效浓度范围为0.0003 - 0.01 μ M，具有良好的细胞毒性特征（选择性指数范围为458 - 2，600）。这些4 ' -E类似物还抑制各种耐药HIV-1克隆的复制，包括HIV-1、HIV-1 K（65 R）、HIV-1（L74 V）、HIV-1（M41/T69 S-S-G/T215 Y）和HIV-1（A62 V/V75 I/F77 L/F116 Y/Q151 M）。此外，这些类似物抑制了携带多种耐药相关氨基酸取代的多药耐药临床HIV-1菌株的复制，这些氨基酸取代是从HIV-1感染者中分离出来的，10或11种不同的抗HIV-1药物对这些HIV-1感染者无效。4 ' -E类似物也阻断非核苷逆转录酶抑制剂抗性克隆HIV-1（Y181 C）的复制，并在药物添加时间测定中显示出与齐多夫定相似的HIV-1抑制谱。4 ' -E-胸苷和4 ' -E-dC的抗病毒活性分别被胸苷和2 ' -脱氧胞苷阻断，而4 ' -E-dA的抗病毒活性不受2 ' -脱氧腺苷的影响，类似于2 '，3 ' -双脱氧核苷的抗病毒活性逆转特征，这强烈表明4 ′-E类似物属于核苷逆转录酶抑制剂家族。进一步开发4 ' -E类似物作为多药耐药HIV-1感染的潜在治疗剂是必要的。
A series of 4 ' -ethynyl (4 ' -E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4 ' -E-2 ' -deoxycytidine (4 ' -E-dC), 4 ' -E-2 ' -deoxyadenosine (4 ' -E-dA), 4 ' -E-2 ' -deoxyribofuranosyl-2,6-diamifiopurine and 4 ' -E-2 ' -deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 muM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4 ' -E analogs also suppressed replication of various drug-resistant HIV-I clones, including HIV-I,,,,,, HIV-1K(65R), HIV-1(L74V), HIV-1(M41/T69S-S-G/T215Y), and HIV-1(A62V/V75I/F77L/F116Y/Q151M). Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4 ' -E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1(Y181C), and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4 ' -E-thymidine and 4 ' -E-dC was blocked by the addition of thymidine and 2 ' -deoxycytidine, respectively, while that of 4 ' -E-dA was not affected by 2 ' -deoxyadenosine, similar to the antiviral activity reversion feature of 2 ' ,3 ' -dideoxynucleosides, strongly suggesting that 4 ' -E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4 ' -E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.