title: Allosteric inhibition of HIV-1 integrase activity.
abstract: HIV-1 integrase is an important therapeutic target in the fight against HIV/AIDS. Integrase strand transfer inhibitors (INSTIs), which target the enzyme active site, have witnessed clinical success over the past 5 years, but the generation of drug resistance poses challenges to INSTI-based therapies moving forward. Integrase is a dynamic protein, and its ordered multimerization is critical to enzyme activity. The integrase tetramer, bound to viral DNA, interacts with host LEDGF/p75 protein to tether integration to active genes. Allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase disrupt integrase assembly with viral DNA and allosterically inhibit enzyme function. ALLINIs display steep dose response curves and synergize with INSTIs ex vivo, highlighting this novel inhibitor class for clinical development.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, CLS-1010, Boston, MA 02215, USA. alan_engelman@dfci.harvard.edu
authors: Alan
authors: A
authors: Engelman
authors: Jacques J
authors: JJ
authors: Kessl
authors: Mamuka
authors: M
authors: Kvaratskhelia
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D020134:Catalytic Domain; D003593:Cytoplasm / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
references: Nat Rev Microbiol. 2012 Mar 16;10(4):279-90
references: 22421880
references: J Biol Chem. 2012 Nov 30;287(49):40858-66
references: 23043109
references: J Biol Chem. 2012 Jun 15;287(25):21189-203
references: 22535962
references: J Biol Chem. 2008 Nov 14;283(46):31802-12
references: 18801737
references: Nat Chem Biol. 2010 Jun;6(6):442-8
references: 20473303
references: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17308-13
references: 16260736
references: J Virol. 2006 Dec;80(23):11498-509
references: 16987986
references: J Biol Chem. 2012 May 11;287(20):16801-11
references: 22437836
references: Nat Med. 2008 Jul;14(7):762-6
references: 18552857
references: Front Microbiol. 2011 Oct 13;2:210
references: 22016749
references: ChemMedChem. 2011 Feb 7;6(2):228-41
references: 21275045
references: Retrovirology. 2012 Oct 09;9:84
references: 23046603
references: Mol Pharmacol. 2009 Oct;76(4):824-32
references: 19638533
references: Structure. 2012 Nov 7;20(11):1918-28
references: 23000384
references: Bioorg Med Chem Lett. 2012 May 1;22(9):3109-14
references: 22483582
references: Virology. 2011 Mar 15;411(2):194-205
references: 21216426
references: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15910-5
references: 20733078
references: Nature. 2010 Nov 11;468(7321):326-9
references: 21068843
references: Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006890
references: 22762018
references: Antimicrob Agents Chemother. 2012 Aug;56(8):4365-74
references: 22664975
references: Nat Struct Mol Biol. 2005 Jun;12(6):526-32
references: 15895093
references: Curr Opin Infect Dis. 2013 Feb;26(1):43-9
references: 23242340
references: Science. 2006 Oct 20;314(5798):461-4
references: 16959972
references: Biochemistry. 2001 Nov 20;40(46):13840-8
references: 11705373
references: J Biol Chem. 2004 Nov 19;279(47):48883-92
references: 15371438
references: AIDS Rev. 2012 Jan-Mar;14(1):17-27
references: 22297501
references: PLoS Pathog. 2009 Jul;5(7):e1000515
references: 19609359
references: Nucleic Acids Res. 2011 Nov 1;39(20):9009-22
references: 21771857
references: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8690-5
references: 23610442
references: PLoS Pathog. 2011 Mar;7(3):e1001313
references: 21423673
references: Nature. 2010 Mar 11;464(7286):232-6
references: 20118915
references: J Virol. 2013 Jan;87(1):648-58
references: 23097450
references: EMBO J. 2012 Jun 29;31(13):3020-8
references: 22580823
references: FEBS Lett. 2008 Apr 30;582(10):1425-30
references: 18331842
references: Virology. 2007 Mar 30;360(1):1-5
references: 17258258
references: BMC Med. 2012 Apr 12;10:34
references: 22498430
references: Ann N Y Acad Sci. 2011 Mar;1222:83-9
references: 21434946
references: Proc Natl Acad Sci U S A. 2007 May 15;104(20):8316-21
references: 17488811
references: Nucleic Acids Res. 2012 Dec;40(22):11518-30
references: 23042676
references: PLoS Pathog. 2012;8(3):e1002558
references: 22396646