Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes

被引:178
作者
Hightower, Kendra E. [1 ]
Wang, Ruolan [1 ]
DeAnda, Felix [1 ]
Johns, Brian A. [1 ]
Weaver, Kurt [1 ]
Shen, Yingnian [1 ]
Tomberlin, Ginger H. [1 ]
Carter, H. Luke, III [1 ]
Broderick, Timothy [1 ]
Sigethy, Scott [1 ]
Seki, Takahiro [2 ]
Kobayashi, Masanori [2 ]
Underwood, Mark R. [1 ]
机构
[1] GlaxoSmithKline, Res Triangle Pk, NC USA
[2] Shionogi & Co Ltd, Osaka, Japan
关键词
STRAND TRANSFER INHIBITORS; PHARMACOLOGICAL ANALYSES; VIRUS; INFECTION; THERAPY; BINDING; REPLICATION; MUTATIONS; MECHANISM; KINETICS;
D O I
10.1128/AAC.00157-11
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 x 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.
引用
收藏
页码:4552 / 4559
页数:8
相关论文
共 48 条
[21]   Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles [J].
Goethals, Olivia ;
Vos, Ann ;
Van Ginderen, Marcia ;
Geluykens, Peggy ;
Smits, Veerle ;
Schols, Dominique ;
Hertogs, Kurt ;
Clayton, Reginald .
VIROLOGY, 2010, 402 (02) :338-346
[22]  
Grobler JA, 2009, 10 INT WORKSH CLIN P
[23]   Scintillation proximity assays for mechanistic and pharmacological analyses of HIV-1 integration [J].
Grobler, Jay A. ;
Stillmock, Kara A. ;
Hazuda, Daria J. .
METHODS, 2009, 47 (04) :249-253
[24]   Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572) [J].
Hare, Stephen ;
Smith, Steven J. ;
Metifiot, Mathieu ;
Jaxa-Chamiec, Albert ;
Pommier, Yves ;
Hughes, Stephen H. ;
Cherepanov, Peter .
MOLECULAR PHARMACOLOGY, 2011, 80 (04) :565-572
[25]   Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance [J].
Hare, Stephen ;
Vos, Ann M. ;
Clayton, Reginald F. ;
Thuring, Jan W. ;
Cummings, Maxwell D. ;
Cherepanov, Peter .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (46) :20057-20062
[26]   Retroviral intasome assembly and inhibition of DNA strand transfer [J].
Hare, Stephen ;
Gupta, Saumya Shree ;
Valkov, Eugene ;
Engelman, Alan ;
Cherepanov, Peter .
NATURE, 2010, 464 (7286) :232-U108
[27]   Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells [J].
Hazuda, DJ ;
Felock, P ;
Witmer, M ;
Wolfe, A ;
Stillmock, K ;
Grobler, JA ;
Espeseth, A ;
Gabryelski, L ;
Schleif, W ;
Blau, C ;
Miller, MD .
SCIENCE, 2000, 287 (5453) :646-650
[28]  
HLUHANICH R, 2010, 49 INT C ANT AG CHEM
[29]  
JOHNS B, 2010, 17 C RETR OPP INF
[30]   In Vitro Antiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor [J].
Kobayashi, Masanori ;
Yoshinaga, Tomokazu ;
Seki, Takahiro ;
Wakasa-Morimoto, Chiaki ;
Brown, Kevin W. ;
Ferris, Robert ;
Foster, Scott A. ;
Hazen, Richard J. ;
Miki, Shigeru ;
Suyama-Kagitani, Akemi ;
Kawauchi-Miki, Shinobu ;
Taishi, Teruhiko ;
Kawasuji, Takashi ;
Johns, Brian A. ;
Underwood, Mark R. ;
Garvey, Edward P. ;
Sato, Akihiko ;
Fujiwara, Tamio .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (02) :813-821