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
[1]   HIV-1 integrase: Structural organization, conformational changes, and catalysis [J].
Asante-Appiah, E ;
Skalka, AM .
ADVANCES IN VIRUS RESEARCH, VOL 52, 1999, 52 :351-369
[2]   Synthesis and HIV-integrase strand transfer inhibition activity of 7-hydroxy[1,3]thiazolo[5,4-b]pyridin-5(4H)-ones [J].
Boros, Eric E. ;
Johns, Brian A. ;
Garvey, Edward P. ;
Koble, Cecilia S. ;
Miller, Wayne H. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (21) :5668-5672
[3]  
Ceccherini-Silberstein F, 2009, AIDS REV, V11, P17
[4]   Structure and function of HIV-1 integrase [J].
Chiu, TK ;
Davies, DR .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (09) :965-977
[5]   Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection [J].
Cooper, David A. ;
Steigbigel, Roy T. ;
Gatell, Jose M. ;
Rockstroh, Jurgen K. ;
Katlama, Christine ;
Yeni, Patrick ;
Lazzarin, Adriano ;
Clotet, Bonaventura ;
Kumar, Princy N. ;
Eron, Joseph E. ;
Schechter, Mauro ;
Markowitz, Martin ;
Loutfy, Mona R. ;
Lennox, Jeffrey L. ;
Zhao, Jing ;
Chen, Joshua ;
Ryan, Desmond M. ;
Rhodes, Rand R. ;
Killar, John A. ;
Gilde, Lucinda R. ;
Strohmaier, Kim M. ;
Meibohm, Anne R. ;
Miller, Michael D. ;
Hazuda, Daria J. ;
Nessly, Michael L. ;
DiNubile, Mark J. ;
Isaacs, Robin D. ;
Teppler, Hedy ;
Nguyen, Bach-Yen .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (04) :355-365
[6]   Opinion - Drug-target residence time and its implications for lead optimization [J].
Copeland, Robert A. ;
Pompliano, David L. ;
Meek, Thomas D. .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :730-739
[7]   HIV integrase, a brief overview from chemistry to therapeutics [J].
Craigie, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (26) :23213-23216
[8]  
Deanda FG, 2010, ANTIVIR THER, V15, pA73
[9]  
DeAnda FG, 2010, 50 INT C ANT AG CHEM
[10]  
DeJesus E., 2007, 4 INT AIDS SOC C HIV