title: Peptide design for antimicrobial and immunomodulatory applications.
abstract: The increasing threat of antibiotic resistance in pathogenic bacteria and the dwindling supply of antibiotics available to combat these infections poses a significant threat to human health throughout the world. Antimicrobial peptides (AMPs) have long been touted as the next generation of antibiotics capable of filling the anti-infective void. Unfortunately, peptide-based antibiotics have yet to realize their potential as novel pharmaceuticals, in spite of the immense number of known AMP sequences and our improved understanding of their antibacterial mechanism of action. Recently, the immunomodulatory properties of certain AMPs have become appreciated. The ability of small synthetic peptides to protect against infection in vivo has demonstrated that modulation of the innate immune response is an effective strategy to further develop peptides as novel anti-infectives. This review focuses on the screening methods that have been used to assess novel peptide sequences for their antibacterial and immunomodulatory properties. It will also examine how we have progressed in our ability to identify and optimize peptides with desired biological characteristics and enhanced therapeutic potential. In addition, the current challenges to the development of peptides as anti-infectives are examined and the strategies being used to overcome these issues are discussed.
authors.affiliation: Centre for Microbial Diseases and Immunity Research, University of British Columbia, 2259 Lower Mall Research Station, Vancouver, British Columbia, Canada V6T 1Z4.
authors.forename: Evan F
authors.initials: EF
authors.lastname: Haney
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D001419:Bacteria / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides
keywords: antimicrobial peptides; host defense peptides; immunomodulatory peptides
references.citation: Proc Natl Acad Sci U S A. 1990 Jun;87(12):4761-5
references.pmid: 1693777
references.citation: Appl Environ Microbiol. 2008 Dec;74(24):7600-6
references.pmid: 18952877
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D933-7
references.pmid: 18957441
references.citation: Curr Pharm Des. 2012;18(6):807-19
references.pmid: 22236127
references.citation: Cell Mol Life Sci. 2011 Jul;68(13):2161-76
references.pmid: 21573784
references.citation: Infect Immun. 2008 Sep;76(9):4176-82
references.pmid: 18591225
references.citation: J Immunol. 2010 Mar 1;184(5):2539-50
references.pmid: 20107187
references.citation: J Immunol. 2009 Aug 15;183(4):2688-96
references.pmid: 19605696
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D590-2
references.pmid: 14681488
references.citation: Nat Protoc. 2008;3(2):163-75
references.pmid: 18274517
references.citation: Peptides. 2010 Nov;31(11):1957-65
references.pmid: 20713107
references.citation: PLoS One. 2013;8(1):e52449
references.pmid: 23308112
references.citation: Antimicrob Agents Chemother. 2012 Jun;56(6):3298-308
references.pmid: 22430978
references.citation: Gene. 2012 Jan 25;492(2):368-74
references.pmid: 22101189
references.citation: Antimicrob Agents Chemother. 2013 Jan;57(1):402-9
references.pmid: 23114765
references.citation: Trends Biotechnol. 2011 Sep;29(9):464-72
references.pmid: 21680034
references.citation: PLoS One. 2011;6(10):e26632
references.pmid: 22039520
references.citation: Trends Biotechnol. 1998 Feb;16(2):82-8
references.pmid: 9487736
references.citation: Expert Opin Drug Deliv. 2012 Oct;9(10):1289-304
references.pmid: 22897647
references.citation: J Am Chem Soc. 2002 Oct 30;124(43):12774-85
references.pmid: 12392424
references.citation: J Immunol. 2002 Oct 1;169(7):3883-91
references.pmid: 12244186
references.citation: Biochim Biophys Acta. 2009 Aug;1788(8):1582-92
references.pmid: 19028449
references.citation: PLoS One. 2013;8(3):e59119
references.pmid: 23555622
references.citation: Mol Microbiol. 2002 Oct;46(1):157-68
references.pmid: 12366839
references.citation: Biochim Biophys Acta. 2006 Sep;1758(9):1184-202
references.pmid: 16756942
references.citation: J Clin Invest. 2009 Sep;119(9):2830-42
references.pmid: 19726870
references.citation: Curr Pharm Des. 2010;16(28):3185-203
references.pmid: 20687878
references.citation: Genome Res. 2005 Apr;15(4):583-9
references.pmid: 15805499
references.citation: Nat Med. 2004 Dec;10(12 Suppl):S122-9
references.pmid: 15577930
references.citation: Chem Biol. 2012 Feb 24;19(2):199-209
references.pmid: 22365603
references.citation: J Infect. 2009 Sep;59 Suppl 1:S40-50
references.pmid: 19766889
references.citation: Vaccine. 2011 Sep 2;29(38):6540-8
references.pmid: 21771625
references.citation: Chem Biol. 2006 Oct;13(10):1101-7
references.pmid: 17052614
references.citation: PLoS One. 2010 Sep 10;5(9):
references.pmid: 20844765
references.citation: Biochem Cell Biol. 2012 Jun;90(3):233-44
references.pmid: 22540735
references.citation: Bioorg Med Chem. 2013 Jan 1;21(1):205-14
references.pmid: 23199484
references.citation: Antimicrob Agents Chemother. 1999 May;43(5):1274-6
references.pmid: 10223951
references.citation: Antimicrob Agents Chemother. 1997 Apr;41(4):771-5
references.pmid: 9087487
references.citation: FEBS Lett. 1990 Nov 12;274(1-2):151-5
references.pmid: 2253768
references.citation: Expert Rev Anti Infect Ther. 2007 Dec;5(6):951-9
references.pmid: 18039080
references.citation: J Innate Immun. 2012;4(4):361-70
references.pmid: 22739631
references.citation: J Immunol Methods. 2002 Sep 1;267(1):13-26
references.pmid: 12135797
references.citation: Vaccine. 2012 Jul 27;30(35):5206-14
references.pmid: 22713718
references.citation: Infect Immun. 2005 Jan;73(1):583-91
references.pmid: 15618198
references.citation: PLoS Negl Trop Dis. 2009;3(2):e373
references.pmid: 19190729
references.citation: Antimicrob Agents Chemother. 2012 May;56(5):2696-704
references.pmid: 22354291
references.citation: PLoS One. 2011;6(8):e24030
references.pmid: 21912615
references.citation: Chem Biol. 2010 Sep 24;17(9):970-80
references.pmid: 20851346
references.citation: J Immunol. 2005 Apr 1;174(7):4271-8
references.pmid: 15778390
references.citation: Biochemistry. 2000 Nov 28;39(47):14504-14
references.pmid: 11087404
references.citation: Antimicrob Agents Chemother. 2011 Oct;55(10):4918-21
references.pmid: 21768519
references.citation: ACS Chem Biol. 2009 Jan 16;4(1):65-74
references.pmid: 19055425
references.citation: Trends Microbiol. 2000 Sep;8(9):402-10
references.pmid: 10989307
references.citation: J Exp Med. 2000 Oct 2;192(7):1069-74
references.pmid: 11015447
references.citation: Int J Oral Sci. 2011 Apr;3(2):55-65
references.pmid: 21485309
references.citation: Chem Biol. 2008 Apr;15(4):354-62
references.pmid: 18420142
references.citation: J Pept Sci. 2006 Oct;12(10):643-52
references.pmid: 16878349
references.citation: Acta Paediatr Jpn. 1994 Oct;36(5):585-91
references.pmid: 7825467
references.citation: Crit Rev Immunol. 2008;28(3):185-200
references.pmid: 19024344
references.citation: J Clin Invest. 2003 Jun;111(11):1665-72
references.pmid: 12782669
references.citation: Peptides. 2012 Aug;36(2):266-71
references.pmid: 22640720
references.citation: Arthritis Res Ther. 2011 Aug 11;13(4):R129
references.pmid: 21835002
references.citation: Int J Antimicrob Agents. 2011 Dec;38 Suppl:11-20
references.pmid: 22018989
references.citation: Peptides. 1999;20(8):963-70
references.pmid: 10503775
references.citation: Nat Rev Drug Discov. 2011 Dec 16;11(1):37-51
references.pmid: 22173434
references.citation: J Med Chem. 2012 Aug 23;55(16):7253-61
references.pmid: 22809409
references.citation: J Biol Chem. 2008 Nov 7;283(45):30471-81
references.pmid: 18765670
references.citation: PLoS One. 2012;7(10):e46476
references.pmid: 23077510
references.citation: J Innate Immun. 2012;4(4):337-48
references.pmid: 22441423
references.citation: J Innate Immun. 2012;4(5-6):553-68
references.pmid: 22722749
references.citation: Sci Transl Med. 2012 May 23;4(135):135ra64
references.pmid: 22623740
references.citation: Biopolymers. 2011;96(1):14-24
references.pmid: 20336731
references.citation: Nat Biotechnol. 2005 Aug;23(8):1008-12
references.pmid: 16041366
references.citation: J Antimicrob Chemother. 2002 Oct;50(4):461-7
references.pmid: 12356789
references.citation: Mol Biosyst. 2009 May;5(5):483-96
references.pmid: 19381363
references.citation: Curr Drug Targets Infect Disord. 2002 Mar;2(1):79-83
references.pmid: 12462155
references.citation: Trends Microbiol. 2005 Jan;13(1):34-40
references.pmid: 15639630
references.citation: Curr Drug Targets. 2012 Aug;13(9):1158-72
references.pmid: 22664075
references.citation: Cell Mol Life Sci. 2011 Jul;68(13):2255-66
references.pmid: 21598022
references.citation: Trends Biotechnol. 2009 Oct;27(10):582-90
references.pmid: 19683819
references.citation: Nat Biotechnol. 2006 Dec;24(12):1551-7
references.pmid: 17160061
references.citation: Clin Diagn Lab Immunol. 2002 Sep;9(5):972-82
references.pmid: 12204946
references.citation: PLoS One. 2012;7(10):e46259
references.pmid: 23056272
references.citation: Nat Rev Drug Discov. 2003 Mar;2(3):214-21
references.pmid: 12612647
references.citation: J Pept Sci. 2008 Jan;14(1):110-4
references.pmid: 17847019
references.citation: PLoS One. 2012;7(8):e39373
references.pmid: 22879874
references.citation: Trends Biotechnol. 1996 Feb;14(2):60-5
references.pmid: 8746118
references.citation: Nat Rev Drug Discov. 2003 Feb;2(2):114-22
references.pmid: 12563302
references.citation: J Leukoc Biol. 2005 Apr;77(4):451-9
references.pmid: 15569695
references.citation: J Immunol. 2003 Dec 15;171(12):6690-6
references.pmid: 14662872
references.citation: J Biol Chem. 2009 Dec 25;284(52):36007-36011
references.pmid: 19850933
references.citation: Peptides. 2006 Apr;27(4):649-60
references.pmid: 16274847
references.citation: Nature. 2001 Nov 22;414(6862):454-7
references.pmid: 11719807
references.citation: Biomaterials. 2011 Jun;32(16):3899-909
references.pmid: 21377727
references.citation: Cell Immunol. 2012 Nov;280(1):22-35
references.pmid: 23246832
references.citation: Nat Biotechnol. 2007 Apr;25(4):465-72
references.pmid: 17384586
references.citation: J Biochem. 2008 Dec;144(6):781-8
references.pmid: 18845567
references.citation: Drug Discov Today. 2005 Jan 1;10(1):45-52
references.pmid: 15676298
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9541-6
references.pmid: 9689116
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5449-53
references.pmid: 3299384
references.citation: Crit Rev Microbiol. 2003;29(3):191-214
references.pmid: 14582617
references.citation: Proc Natl Acad Sci U S A. 1988 Feb;85(3):910-3
references.pmid: 3277183
references.citation: Chem Biol Drug Des. 2007 Aug;70(2):134-42
references.pmid: 17683374
references.citation: Biochim Biophys Acta. 2007 May;1768(5):1160-9
references.pmid: 17320042