title: Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures.
abstract: We have used a novel human retinal pigmented epithelial (RPE) cell-based model that mimics drusen biogenesis and the pathobiology of age-related macular degeneration to evaluate the efficacy of newly designed peptide inhibitors of the complement system. The peptides belong to the compstatin family and, compared to existing compstatin analogs, have been optimized to promote binding to their target, complement protein C3, and to enhance solubility by improving their polarity/hydrophobicity ratios. Based on analysis of molecular dynamics simulation data of peptide-C3 complexes, novel binding features were designed by introducing intermolecular salt bridge-forming arginines at the N-terminus and at position -1 of N-terminal dipeptide extensions. Our study demonstrates that the RPE cell assay has discriminatory capability for measuring the efficacy and potency of inhibitory peptides in a macular disease environment.
authors: Department of Bioengineering, University of California, Riverside, CA 92521, USA.
authors: Ronald D
authors: RD
authors: Gorham
authors: David L
authors: DL
authors: Forest
authors: Phanourios
authors: P
authors: Tamamis
authors: Aliana
authors: A
authors: López de Victoria
authors: Márta
authors: M
authors: Kraszni
authors: Chris A
authors: CA
authors: Kieslich
authors: Christopher D
authors: CD
authors: Banna
authors: Meghan L
authors: ML
authors: Bellows-Peterson
authors: Cynthia K
authors: CK
authors: Larive
authors: Christodoulos A
authors: CA
authors: Floudas
authors: Georgios
authors: G
authors: Archontis
authors: Lincoln V
authors: LV
authors: Johnson
authors: Dimitrios
authors: D
authors: Morikis
mesh_terms: D002478:Cells, Cultured; D003167:Complement Activation; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology*; D015593:Retinal Drusen / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*
chemical_list: D010456:Peptides, Cyclic; C111828:compstatin
keywords: AMD; AP; ApoE; C3; C3b; C3c; C5b-9; ELISA; FB; MD; PDB; RP-HPLC; RPE; age-related macular degeneration; alternative pathway of complement activation; apolipoprotein E; complement inhibitors; complement system; complement system protein 3; compstatin family peptides; drusen; enzyme-linked immunosorbent assay; factor B; macular degeneration; molecular dynamics; protein data bank; retinal pigmented epithelium; reversed phase high performance liquid chromatography; the b-fragment of C3; the c-fragment of C3; the membrane attack complex consisting of complement proteins C5b, C6, C7, C8, and C9(n)
references: Mol Immunol. 2003 Jan;39(10):557-66
references: 12431389
references: Proteins. 2010 Sep;78(12):2655-67
references: 20589629
references: Proteins. 2003 Oct 1;53(1):130-41
references: 12945056
references: Prog Retin Eye Res. 2010 Mar;29(2):95-112
references: 19961953
references: J Biol Chem. 2002 Apr 26;277(17):14942-53
references: 11847226
references: Mol Immunol. 2009 Dec;47(2-3):185-95
references: 19800693
references: Chem Biol Drug Des. 2011 Jun;77(6):431-40
references: 21352502
references: J Mol Recognit. 2009 Nov-Dec;22(6):495-505
references: 19658192
references: Protein Sci. 1998 Mar;7(3):619-27
references: 9541394
references: Nat Biotechnol. 2007 Nov;25(11):1265-75
references: 17989689
references: J Comput Chem. 2012 Jan 15;33(2):189-202
references: 22042689
references: Immunopharmacology. 2000 Jul 20;48(2):199-212
references: 10936517
references: Ophthalmology. 2008 Jun;115(6):1026-31
references: 17981333
references: J Chromatogr A. 2004 May 28;1037(1-2):3-14
references: 15214657
references: Biochem Soc Trans. 2002 Nov;30(Pt 6):1026-36
references: 12440966
references: J Immunol. 1996 Jul 15;157(2):884-91
references: 8752942
references: J Mol Graph Model. 2007 Sep;26(2):571-80
references: 17498990
references: Retina. 2010 Oct;30(9):1350-67
references: 20924259
references: J Comput Chem. 2003 Nov 15;24(14):1691-702
references: 12964188
references: Biophys J. 2010 Nov 17;99(10):3445-53
references: 21081094
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: J Comput Chem. 2004 Aug;25(11):1400-15
references: 15185334
references: Proteins. 2011 Nov;79(11):3166-79
references: 21989937
references: J Comput Chem. 2005 Nov 15;26(14):1452-63
references: 16088926
references: Immunobiology. 2013 Apr;218(4):496-505
references: 22795972
references: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18277-82
references: 21969589
references: J Med Chem. 2006 Jul 27;49(15):4616-22
references: 16854067
references: Biophys Chem. 2005 Apr 1;115(2-3):201-7
references: 15752605
references: Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3612-24
references: 16877436
references: Semin Ophthalmol. 2011 May;26(3):167-80
references: 21609230
references: J Biol Chem. 1987 Apr 5;262(10):4922-7
references: 3549712
references: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references: 24889800
references: Ophthalmology. 2008 Sep;115(9):1474-9, 1479.e1-6
references: 18502512
references: Biochem Soc Trans. 2004 Feb;32(Pt 1):28-32
references: 14748706
references: J Immunol. 2003 Aug 15;171(4):1881-90
references: 12902490
references: Proteins. 2009 Dec;77(4):778-95
references: 19603484
references: J Comput Chem. 2009 Jul 30;30(10):1545-614
references: 19444816
references: Adv Exp Med Biol. 2010;703:127-35
references: 20711711
references: J Am Chem Soc. 2005 Aug 10;127(31):10967-76
references: 16076203
references: Prog Retin Eye Res. 2001 Nov;20(6):705-32
references: 11587915
references: Chem Biol Drug Des. 2012 May;79(5):703-18
references: 22233517
references: Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1200-9
references: 18326750
references: J Med Chem. 2012 May 10;55(9):4159-68
references: 22500977
references: Adv Exp Med Biol. 2008;632:273-92
references: 19025129
references: Am J Ophthalmol. 2001 Jun;131(6):767-81
references: 11384575
references: J Am Chem Soc. 2003 Jul 16;125(28):8422-3
references: 12848533
references: Anal Bioanal Chem. 2009 Jun;394(3):707-29
references: 19184676
references: J Immunol. 2000 Sep 1;165(5):2491-9
references: 10946275
references: J Chromatogr A. 2004 May 28;1037(1-2):299-310
references: 15214672
references: J Med Chem. 2005 Jan 13;48(1):274-86
references: 15634022
references: J Biol Chem. 2007 Oct 5;282(40):29241-7
references: 17684013
references: Biophys J. 2010 May 19;98(10):2337-46
references: 20483343