In Vitro Characterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor

被引：109

作者：

Lai, Ming-Tain ^{[1
]}

Feng, Meizhen ^{[1
]}

Falgueyret, Jean-Pierre ^{[2
]}

Tawa, Paul ^{[2
]}

Witmer, Marc ^{[1
]}

DiStefano, Daniel ^{[1
]}

Li, Yuan ^{[1
]}

Burch, Jason ^{[2
]}

Sachs, Nancy ^{[1
]}

Lu, Meiqing ^{[1
]}

Cauchon, Elizabeth ^{[2
]}

Campeau, Louis-Charles ^{[2
]}

Grobler, Jay ^{[1
]}

Yan, Youwei ^{[1
]}

Ducharme, Yves ^{[2
]}

Cote, Bernard ^{[2
]}

Asante-Appiah, Ernest ^{[2
]}

Hazuda, Daria J. ^{[1
]}

Miller, Michael D. ^{[1
]}

机构：

[1] Merck Res Labs, West Point, PA USA

[2] Merck Frosst Ctr Therapeut Res, Kirkland, PQ, Canada

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2014年 / 58卷 / 03期

关键词：

DRUG-RESISTANCE MUTATIONS; ANTIRETROVIRAL THERAPY; REPLICATION CAPACITY; ANTIVIRAL ACTIVITY; M184I MUTATION; EFAVIRENZ; RILPIVIRINE; RT; AIDS; SUSCEPTIBILITY;

D O I：

10.1128/AAC.02403-13

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 <3. A two-drug in vitro combination study indicated that MK-1439 acts nonantagonistically in the antiviral activity with each of 18 FDA-licensed drugs for HIV infection. Taken together, these in vitro data suggest that MK-1439 possesses the desired properties for further development as a new antiviral agent.

引用

页码：1652 / 1663

页数：12

共 47 条

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