In Vitro Characterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor
In Vitro Characterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor
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DOI：
10.1128/aac.02403-13
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发表时间：
2014-03-01
影响因子：
4.9
通讯作者：
Miller, Michael D.
中科院分区：
文献类型：
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作者：
Lai, Ming-Tain;Feng, Meizhen;Miller, Michael D.
非核苷类逆转录酶抑制剂（NNRTIs）是治疗人类免疫缺陷病毒1型（HIV - 1）感染患者的主要疗法。MK - 1439是一种新型的NNRTI，在生化分析中，其对野生型（WT）以及K103N和Y181C逆转录酶（RT）突变体的半数抑制浓度（IC50）分别为12、9.7和9.7 nM。选择性和细胞毒性研究证实，MK - 1439是一种高度特异性的NNRTI，具有最小的脱靶活性。在50%正常人血清（NHS）存在的情况下，MK - 1439在抑制野生型病毒复制方面表现出优异的效力，95%有效浓度（EC95）为20 nM，对K103N、Y181C和K103N/Y181C突变病毒的EC95分别为43、27和55 nM。MK - 1439对10种不同的HIV - 1亚型病毒（共93种病毒）表现出相似的抗病毒活性。此外，还研究了更广泛的一系列与临床NNRTI相关的突变病毒（共96种病毒）对MK - 1439和其他基准NNRTIs的敏感性。结果表明，MK - 1439的突变谱总体上优于依非韦伦（EFV），与依曲韦林（ETR）和利匹韦林（RPV）相当。此外，与ETR和RPV相关的E138K、Y181C和K101E突变病毒对MK - 1439敏感，其倍数变化（FC）为……
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a mainstay of therapy for treating human immunodeficiency type 1 virus (HIV-1)-infected patients. MK-1439 is a novel NNRTI with a 50% inhibitory concentration (IC50) of 12, 9.7, and 9.7 nM against the wild type (WT) and K103N and Y181C reverse transcriptase (RT) mutants, respectively, in a biochemical assay. Selectivity and cytotoxicity studies confirmed that MK-1439 is a highly specific NNRTI with minimum off-target activities. In the presence of 50% normal human serum (NHS), MK-1439 showed excellent potency in suppressing the replication of WT virus, with a 95% effective concentration (EC95) of 20 nM, as well as K103N, Y181C, and K103N/Y181C mutant viruses with EC95 of 43, 27, and 55 nM, respectively. MK-1439 exhibited similar antiviral activities against 10 different HIV-1 subtype viruses (a total of 93 viruses). In addition, the susceptibility of a broader array of clinical NNRTI-associated mutant viruses (a total of 96 viruses) to MK-1439 and other benchmark NNRTIs was investigated. The results showed that the mutant profile of MK-1439 was superior overall to that of efavirenz (EFV) and comparable to that of etravirine (ETR) and rilpivirine (RPV). Furthermore, E138K, Y181C, and K101E mutant viruses that are associated with ETR and RPV were susceptible to MK-1439 with a fold change (FC) of