title: Ultrashort cationic lipopeptides and lipopeptoids selectively induce cytokine production in macrophages.
abstract: A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Groα and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and NLysGlyNLys sequences did not induce cytokine production, whereas those based on LysLysLys and NLysNLysNLys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-α at or below 100 µM. Two compounds, peptoids C16OH-NLysNLysNLys and C16OH-NHarNHarNHar, were selective for IL-8 production and did not induce TNF-α or IL-1β. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.
authors: Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Brandon
authors: B
authors: Findlay
authors: Neeloffer
authors: N
authors: Mookherjee
authors: Frank
authors: F
authors: Schweizer
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000172:deficiency; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055550:Protein Stability; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D054360:Chemokine CXCL1; D053583:Interleukin-1beta; D016209:Interleukin-8; D055666:Lipopeptides; D034444:Peptoids; D013501:Surface-Active Agents; D014409:Tumor Necrosis Factor-alpha; D054804:Cathelicidins
references: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references: 17159923
references: J Immunol. 2007 Dec 1;179(11):7684-91
references: 18025214
references: Antimicrob Agents Chemother. 1999 Apr;43(4):782-8
references: 10103181
references: PLoS One. 2012;7(7):e41141
references: 22844435
references: Biochim Biophys Acta. 2008 Jul-Aug;1778(7-8):1528-36
references: 18358231
references: Nat Rev Microbiol. 2005 Mar;3(3):238-50
references: 15703760
references: J Leukoc Biol. 2005 Apr;77(4):451-9
references: 15569695
references: J Immunol. 2010 Mar 1;184(5):2539-50
references: 20107187
references: J Immunol. 2009 Aug 15;183(4):2688-96
references: 19605696
references: Emerg Infect Dis. 2007 Nov;13(11):1632-9
references: 18217544
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20595-600
references: 19106303
references: Int J Antimicrob Agents. 2012 Jul;40(1):36-42
references: 22578748
references: Science. 2010 Feb 19;327(5968):1010-3
references: 20167788
references: J Invest Dermatol. 2003 Mar;120(3):379-89
references: 12603850
references: Immunotechnology. 1995 May;1(1):65-72
references: 9373334
references: Int Rev Immunol. 2011 Feb;30(1):16-34
references: 21235323
references: J Med Chem. 2011 Dec 8;54(23):8148-60
references: 22007676
references: Biochemistry. 2008 Oct 7;47(40):10630-6
references: 18783248
references: Front Immunol. 2012 Jun 11;3:149
references: 22701455
references: Int Immunol. 2001 Jul;13(7):933-40
references: 11431423
references: J Pathol. 2008 Jan;214(2):149-60
references: 18161752
references: J Org Chem. 2000 Dec 29;65(26):9054-8
references: 11149851
references: Antimicrob Agents Chemother. 2006 Jul;50(7):2316-22
references: 16801407
references: ACS Chem Biol. 2012 Jul 20;7(7):1281-91
references: 22594381
references: Emerg Infect Dis. 2012 May;18(5):741-9
references: 22515968
references: J Exp Med. 2000 Oct 2;192(7):1069-74
references: 11015447
references: Biochemistry. 2004 Jul 6;43(26):8459-69
references: 15222757
references: Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9367-71
references: 1409642
references: Infect Immun. 1995 Apr;63(4):1291-7
references: 7890387
references: Cell Mol Life Sci. 2011 Jul;68(13):2161-76
references: 21573784
references: Nat Rev Microbiol. 2012 Mar 16;10(4):243-54
references: 22421877
references: Mol Biosyst. 2009 May;5(5):483-96
references: 19381363
references: Antimicrob Agents Chemother. 2010 Oct;54(10):4049-58
references: 20696877
references: ACS Chem Biol. 2011 Jun 17;6(6):658-66
references: 21438496
references: Cytokine. 2008 Oct;44(1):1-8
references: 18722135
references: J Am Chem Soc. 2012 Jul 11;134(27):11088-91
references: 22697149
references: J Immunol. 2011 Jun 15;186(12):7127-35
references: 21602493
references: Nat Biotechnol. 2007 Apr;25(4):465-72
references: 17384586
references: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5449-53
references: 3299384
references: J Immunol. 2006 Feb 15;176(4):2455-64
references: 16456005