title: Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes.
abstract: The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10(-6) s(-1) and a dissociative half-life (t(1/2)) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t(1/2), at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.
authors.affiliation: Infectious Diseases MDD, 3.2104 GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA.
authors.forename: Kendra E
authors.initials: KE
authors.lastname: Hightower
authors.forename: Ruolan
authors.initials: R
authors.lastname: Wang
authors.forename: Felix
authors.initials: F
authors.lastname: Deanda
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Kurt
authors.initials: K
authors.lastname: Weaver
authors.forename: Yingnian
authors.initials: Y
authors.lastname: Shen
authors.forename: Ginger H
authors.initials: GH
authors.lastname: Tomberlin
authors.forename: H Luke
authors.initials: HL
authors.lastname: Carter
authors.forename: Timothy
authors.initials: T
authors.lastname: Broderick
authors.forename: Scott
authors.initials: S
authors.lastname: Sigethy
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Underwood
mesh_terms: D019943:Amino Acid Substitution; D018076:DNA, Complementary; D004279:DNA, Viral / Q000378:metabolism*; D024882:Drug Resistance, Viral; D005838:Genotype; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism* / Q000494:pharmacology; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000378:metabolism* / Q000494:pharmacology; D015363:Quinolones / Q000378:metabolism* / Q000494:pharmacology; D000068898:Raltegravir Potassium; D000099226:Dolutegravir
chemical_list: D018076:DNA, Complementary; D004279:DNA, Viral; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir