title: Mechanistic insights into the enhancement of adeno-associated virus transduction by proteasome inhibitors.
abstract: Proteasome inhibitors (e.g., bortezomib, MG132) are known to enhance adeno-associated virus (AAV) transduction; however, whether this results from pleotropic proteasome inhibition or off-target serine and/or cysteine protease inhibition remains unresolved. Here, we examined recombinant AAV (rAAV) effects of a new proteasome inhibitor, carfilzomib, which specifically inhibits chymotrypsin-like proteasome activity and no other proteases. We determined that proteasome inhibitors act on rAAV through proteasome inhibition and not serine or cysteine protease inhibition, likely through positive changes late in transduction.
authors.affiliation: Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Mitchell
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
mesh_terms: D002460:Cell Line; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D000229:Dependovirus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010322:Parvoviridae Infections / Q000201:enzymology / Q000821:virology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D014161:Transduction, Genetic
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D002918:Chymotrypsin
references.citation: J Clin Invest. 2000 Jun;105(11):1573-87
references.pmid: 10841516
references.citation: Curr Gene Ther. 2010 Oct;10(5):319-340
references.pmid: 20712583
references.citation: Cancer Res. 2007 Jul 1;67(13):6383-91
references.pmid: 17616698
references.citation: Acta Pharmacol Sin. 2004 Feb;25(2):196-202
references.pmid: 14769209
references.citation: Mol Ther. 2007 Apr;15(4):764-71
references.pmid: 17299410
references.citation: Curr Top Microbiol Immunol. 2002;268:185-208
references.pmid: 12083006
references.citation: Mol Ther Nucleic Acids. 2013 Feb 05;2:e70
references.pmid: 23385523
references.citation: Cancer Res. 1999 Jun 1;59(11):2615-22
references.pmid: 10363983
references.citation: J Biochem. 1996 Mar;119(3):572-6
references.pmid: 8830056
references.citation: J Biol Chem. 2002 Apr 19;277(16):14060-7
references.pmid: 11821413
references.citation: Virology. 2011 Sep 1;417(2):327-33
references.pmid: 21752418
references.citation: J Virol. 2004 Mar;78(6):2863-74
references.pmid: 14990705
references.citation: Mol Ther. 2010 Nov;18(11):1907-16
references.pmid: 20700109
references.citation: Gene Ther. 2013 Mar;20(3):308-17
references.pmid: 22622241
references.citation: J Virol. 2013 Aug;87(15):8675-86
references.pmid: 23740985
references.citation: Nat Protoc. 2006;1(3):1412-28
references.pmid: 17406430
references.citation: Blood. 2012 Jan 26;119(4):957-66
references.pmid: 22134170
references.citation: J Virol. 2013 Apr;87(8):4571-83
references.pmid: 23408604
references.citation: Virology. 2008 Nov 25;381(2):194-202
references.pmid: 18834608
references.citation: Gene Ther. 2011 Feb;18(2):128-34
references.pmid: 20844567
references.citation: J Gene Med. 2005 Nov;7(11):1429-38
references.pmid: 15945124
references.citation: Hepatogastroenterology. 2013 Jun;60(124):837-41
references.pmid: 23732779
references.citation: J Virol. 1996 May;70(5):3227-34
references.pmid: 8627803
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5719-23
references.pmid: 7777575
references.citation: Nat Rev Genet. 2003 Jul;4(7):544-58
references.pmid: 12838346
references.citation: Mol Ther. 2005 Apr;11(4):600-7
references.pmid: 15771962
references.citation: J Virol. 2002 Nov;76(22):11530-40
references.pmid: 12388714
references.citation: Clin Cancer Res. 2011 May 1;17(9):2734-43
references.pmid: 21364033
references.citation: Gene Ther. 2012 Apr;19(4):375-84
references.pmid: 21776025
references.citation: J Virol. 2009 Mar;83(6):2632-44
references.pmid: 19109385
references.citation: Expert Opin Biol Ther. 2013 Jun;13 Suppl 1:S1-22
references.pmid: 23692500
references.citation: J Virol. 2005 Aug;79(15):9933-44
references.pmid: 16014954
references.citation: J Virol. 2002 Mar;76(5):2043-53
references.pmid: 11836382
references.citation: PLoS Pathog. 2011 May;7(5):e1002053
references.pmid: 21625534
references.citation: Mol Ther. 2007 Feb;15(2):330-9
references.pmid: 17235311
references.citation: Gene Ther. 2005 Oct;12(20):1534-8
references.pmid: 15944729
references.citation: Bioorg Med Chem Lett. 1999 Aug 2;9(15):2283-8
references.pmid: 10465562
references.citation: Blood. 2007 Nov 1;110(9):3281-90
references.pmid: 17591945
references.citation: J Virol. 2001 Feb;75(4):1824-33
references.pmid: 11160681
references.citation: Gene Ther. 2009 Jan;16(1):60-9
references.pmid: 18701909
references.citation: J Virol. 2003 Jul;77(13):7361-6
references.pmid: 12805434
references.citation: Mol Ther. 2007 Jul;15(7):1323-30
references.pmid: 17440440
references.citation: J Genet Syndr Gene Ther. 2012 Jan 18;1:1-9
references.pmid: 23565343