title: In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor.
abstract: 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.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Meizhen
authors.initials: M
authors.lastname: Feng
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Paul
authors.initials: P
authors.lastname: Tawa
authors.forename: Marc
authors.initials: M
authors.lastname: Witmer
authors.forename: Daniel
authors.initials: D
authors.lastname: DiStefano
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Jason
authors.initials: J
authors.lastname: Burch
authors.forename: Nancy
authors.initials: N
authors.lastname: Sachs
authors.forename: Meiqing
authors.initials: M
authors.lastname: Lu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.forename: Jay
authors.initials: J
authors.lastname: Grobler
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004357:Drug Synergism; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D011728:Pyridones / Q000009:adverse effects / Q000494:pharmacology*; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011728:Pyridones; D014230:Triazoles; C000592662:doravirine; D054303:HIV Reverse Transcriptase