title: The small-molecule 3G11 inhibits HIV-1 reverse transcription.
abstract: The small-molecule 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (3G11) inhibits HIV-1 replication in the human T cell line MT-2. Here, we showed that 3G11 specifically and potently blocks HIV-1 infection. By contrast, 3G11 did not block other retroviruses such as HIV-2, simian immunodeficiency virus (SIVmac), bovine immunodeficiency virus, feline immunodeficiency virus, equine infectious anemia virus, N-tropic murine leukemia virus, B-tropic murine leukemia virus, and Moloney murine leukemia virus. Analysis of DNA metabolism by real-time PCR revealed that 3G11 blocks the formation of HIV-1 late reverse transcripts during infection prior to the first-strand transfer step. In agreement, an in vitro assay revealed that 3G11 blocks the enzymatic activity of HIV-1 reverse transcriptase as strong as nevirapine. Docking of 3G11 to the HIV-1 reverse transcriptase enzyme suggested a direct interaction between residue L100 and 3G11. In agreement, an HIV-1 virus bearing the reverse transcriptase change L100I renders HIV-1 resistant to 3G11, which suggested that the reverse transcriptase enzyme is the viral determinant for HIV-1 sensitivity to 3G11. Although NMR experiments revealed that 3G11 binds to the HIV-1 capsid, functional experiments suggested that capsid is not the viral determinant for sensitivity to 3G11. Overall, we described a novel non-nucleoside reverse transcription inhibitor that blocks HIV-1 infection.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Silvana
authors.initials: S
authors.lastname: Opp
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fricke
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Shepard
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kovalskyy
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Akash
authors.identifier: 0000-0001-8748-9969
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Herkules
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Dmitri N
authors.initials: DN
authors.lastname: Ivanov
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Valle-Casuso
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000621037:6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: HIV-1; L100; NNRTI; antiviral drug; capsid; reverse transcription