title: Antiviral activity and in vitro mutation development pathways of MK-6186, a novel nonnucleoside reverse transcriptase inhibitor.
abstract: MK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations, in vitro resistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Meiqing
authors.initials: M
authors.lastname: Lu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Vandna
authors.initials: V
authors.lastname: Munshi
authors.forename: Renee C
authors.initials: RC
authors.lastname: Hrin
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Wang
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Robert
authors.initials: R
authors.lastname: Gomez
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Anthony
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: Jay A
authors.initials: JA
authors.lastname: Grobler
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Philip M
authors.initials: PM
authors.lastname: McKenna
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz