Design of a bioactive cell-penetrating peptide: when a transduction domain does more than transduce.
The discovery of cell-penetrating peptides (CPPs) has facilitated delivery of peptides into cells to affect cellular behavior. Previously, we were successful at developing a phosphopeptide mimetic of the small heat shock-like protein HSP20 . Building on this success we developed a cell-permeant peptide inhibitor of mitogen-activated protein kinase-activated protein kinase 2 (MK2). It is well documented that inhibition of MK2 may be beneficial for a myriad of human diseases including those involving inflammation and fibrosis. During the optimization of the activity and specificity of the MK2 inhibitor (MK2i) we closely examined the effect of cell-penetrating peptide identity. Surprisingly, the identity of the CPP dictated kinase specificity and functional activity to an extent that rivaled that of the therapeutic peptide. The results reported herein have wide implications for delivering therapeutics with CPPs and indicate that judicious choice of CPP is crucial to the ultimate therapeutic success.
Ward
Brian
B
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907-2032, USA.
Seal
Brandon L
BL
Brophy
Colleen M
CM
Panitch
Alyssa
A
D000595:Amino Acid Sequence; D002470:Cell Survival; D002478:Cells, Cultured; D015195:Drug Design; D004847:Epithelial Cells; D050886:HSP20 Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000099190:MAP-Kinase-Activated Kinase 2
D050886:HSP20 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2
J Biol Chem. 2001 Feb 23;276(8):5836-40
11084031
Blood. 1994 Apr 1;83(7):1791-8
8142647
Cell Signal. 2000 Jan;12(1):1-13
10676842
J Biol Chem. 1994 Apr 8;269(14):10444-50
8144628
Gene Ther. 2002 Nov;9(21):1422-8
12378404
FEBS Lett. 1996 Oct 21;395(2-3):133-6
8898080
Cell. 1994 Sep 23;78(6):1027-37
7923353
Biochem J. 1993 Dec 15;296 ( Pt 3):843-9
8280084
Curr Med Chem. 2007;14(21):2214-34
17896971
Bioconjug Chem. 2004 May-Jun;15(3):482-90
15149175
Nat Biotechnol. 2005 Mar;23(3):329-36
15711537
Biochem Biophys Res Commun. 2009 May 8;382(3):535-9
19289101
J Exp Med. 2007 Jul 9;204(7):1637-52
17576778
Biochem Soc Trans. 2002 Nov;30(Pt 6):959-63
12440954
FEBS Lett. 1996 Sep 2;392(3):209-14
8774846
Eur J Neurosci. 2008 Aug;28(4):642-54
18702688
Leukemia. 1995 Feb;9(2):288-94
7869766
Biochem J. 2003 Apr 1;371(Pt 1):199-204
12534346
Methods. 2001 Jul;24(3):247-56
11403574
Cell. 1988 Dec 23;55(6):1189-93
2849510
J Biol Chem. 2002 Nov 8;277(45):42596-602
12202485
J Exp Med. 2002 Dec 16;196(12):1563-74
12486099
Nat Methods. 2007 Feb;4(2):119-20
17264857
J Biol Chem. 1995 Jun 16;270(24):14255-8
7782278
J Pept Res. 2000 Nov;56(5):318-25
11095185
J Immunol. 2006 Aug 1;177(3):1913-7
16849504
Trends Mol Med. 2007 Oct;13(10):443-8
17913584
Front Biosci. 2008 May 01;13:5511-21
18508601
J Cell Sci. 1997 Feb;110 ( Pt 3):357-68
9057088
EMBO J. 2002 Oct 15;21(20):5396-407
12374740
Arch Biochem Biophys. 1996 Oct 15;334(2):206-13
8900394
Bioconjug Chem. 2004 Nov-Dec;15(6):1246-53
15546190
Mol Cell. 2005 Jan 7;17(1):37-48
15629715
Nat Rev Mol Cell Biol. 2006 Feb;7(2):120-30
16421520
Biochemistry. 2002 Oct 22;41(42):12652-61
12379107
J Med Chem. 2002 Aug 15;45(17):3612-8
12166934
Biochem Biophys Res Commun. 1994 Apr 29;200(2):1118-24
8179591
J Immunol. 2002 May 1;168(9):4667-73
11971016
J Biol Chem. 1996 Apr 5;271(14):8488-92
8626550
Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1298-306
16423921
FASEB J. 2003 Jul;17(10):1358-60
12738803
Nat Cell Biol. 2004 Mar;6(3):189-96
15039791
FASEB J. 2005 Feb;19(2):261-3
15598710
Biochem Pharmacol. 1997 May 9;53(9):1239-47
9214684
Trends Cell Biol. 2000 Jul;10(7):290-5
10856932
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14772-7
11121077
Nat Biotechnol. 2008 Jan;26(1):127-32
18183025
J Med Chem. 1999 Mar 11;42(5):910-9
10072688
Biomacromolecules. 2003 Nov-Dec;4(6):1572-82
14606882
J Biol Chem. 2006 Aug 18;281(33):23658-67
16774924
Cancer Res. 2001 Jan 15;61(2):474-7
11212234
Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1864-8
1672046
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13003-8
11087855
Cancer Cell. 2007 Feb;11(2):175-89
17292828
Cell. 1988 Dec 23;55(6):1179-88
2849509
Curr Opin Biotechnol. 2002 Feb;13(1):52-6
11849958
J Biol Chem. 2002 Oct 4;277(40):37401-5
12171911
Nat Cell Biol. 1999 Jun;1(2):94-7
10559880
Mol Pharmacol. 1994 Dec;46(6):1077-83
7808427
Circ Res. 2007 Nov 26;101(11):1104-12
17885219
Microbiol Mol Biol Rev. 2004 Jun;68(2):320-44
15187187
Curr Pharm Des. 2005;11(28):3597-611
16305497
Trends Cell Biol. 1998 Feb;8(2):84-7
9695814
Arch Biochem Biophys. 2002 Jan 15;397(2):224-31
11795875
J Cell Biochem. 1995 Feb;57(2):321-30
7759569