title: Small-molecule costimulatory blockade: organic dye inhibitors of the CD40-CD154 interaction.
abstract: Costimulatory blockade is one of the most promising therapeutic targets in autoimmune diseases as well as in transplant recipients, and inhibition of the cluster of differentiation (CD)40-CD154 interaction, which is required for T cell activation and development of an effective immune response, is particularly promising in islet transplant recipients. Here, we report the ability of several small-molecule organic dyes to concentration dependently inhibit this interaction with IC(50) values in the low-micromolar range. They were found to be considerably more active in inhibiting this interaction than the tumor necrosis factor (TNF)-R1-TNF-alpha or B cell-activating factor (BAFF)-R-BAFF interaction, which are members of the same family. They specifically inhibited CD154-induced cell responses in human B cells as well as in THP-1 myeloid cells, which can serve as surrogate dendritic cells, at concentrations well below their cytotoxic concentrations determined in the same cells. Flow cytometry experiments confirmed their ability to inhibit the CD154-induced, but not the Staphylococcus aureus Cowan I- or phorbol 12-myristate 13-acetate-induced increase in the surface expression of CD54, CD40, and major histocompatibility complex class II. Accordingly, these compounds can be useful not only for experimental investigations involving the inhibition of the CD40-CD154 costimulatory interaction but can also provide important structure-activity relationship information and can serve as the starting point of a targeted drug discovery program.
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Emilio
authors.initials: E
authors.lastname: Margolles-Clark
authors.forename: Oliver
authors.initials: O
authors.lastname: Umland
authors.forename: Norma S
authors.initials: NS
authors.lastname: Kenyon
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D004396:Coloring Agents / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects
chemical_list: D019013:CD40 Antigens; D004396:Coloring Agents; D007166:Immunosuppressive Agents; D023201:CD40 Ligand
references.citation: Biochem Pharmacol. 2009 Apr 1;77(7):1236-45
references.pmid: 19283894
references.citation: Protein Eng Des Sel. 2007 Mar;20(3):133-41
references.pmid: 17307885
references.citation: J Pept Res. 2005 Jun;65(6):591-604
references.pmid: 15885118
references.citation: Annu Rev Immunol. 2004;22:307-28
references.pmid: 15032580
references.citation: J Biomol Screen. 2008 Jun;13(5):415-23
references.pmid: 18490662
references.citation: Cell Mol Life Sci. 2001 Jan;58(1):4-43
references.pmid: 11229815
references.citation: Clin Exp Immunol. 1981 Feb;43(2):260-9
references.pmid: 7273480
references.citation: J Clin Invest. 2004 Oct;114(7):979-87
references.pmid: 15467837
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8132-7
references.pmid: 10393960
references.citation: Immunol Rev. 2009 May;229(1):271-93
references.pmid: 19426228
references.citation: Mol Immunol. 2008 Feb;45(4):937-44
references.pmid: 17959249
references.citation: J Comput Aided Mol Des. 2006 Feb;20(2):109-30
references.pmid: 16622794
references.citation: Mod Rheumatol. 2005;15(6):423-6
references.pmid: 17029106
references.citation: Curr Top Med Chem. 2007;7(10):928-42
references.pmid: 17508924
references.citation: Nature. 2007 Dec 13;450(7172):1001-9
references.pmid: 18075579
references.citation: Infect Immun. 1999 Nov;67(11):5573-8
references.pmid: 10531202
references.citation: Nat Rev Immunol. 2004 Apr;4(4):259-68
references.pmid: 15057784
references.citation: Diabetes. 2006 Sep;55(9):2437-45
references.pmid: 16936191
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):301-17
references.pmid: 15060526
references.citation: J Physiol Pharmacol. 1993 Sep;44(3):213-32
references.pmid: 8241524
references.citation: J Toxicol Sci. 2008 Feb;33(1):71-83
references.pmid: 18303186
references.citation: J Periodontal Res. 1999 May;34(4):203-13
references.pmid: 10444744
references.citation: J Med Chem. 2002 Apr 11;45(8):1712-22
references.pmid: 11931626
references.citation: J Biol Chem. 1998 Sep 18;273(38):24603-9
references.pmid: 9733755
references.citation: Clin Microbiol Rev. 2005 Jul;18(3):521-40
references.pmid: 16020688
references.citation: J Mol Med (Berl). 2009 Feb;87(2):181-97
references.pmid: 18985310
references.citation: Nat Med. 2000 Feb;6(2):114
references.pmid: 10655072
references.citation: Nat Protoc. 2006;1(2):550-3
references.pmid: 17191086
references.citation: Biochemistry. 2001 Nov 13;40(45):13520-8
references.pmid: 11695899
references.citation: Br J Haematol. 1956 Jul;2(3):276-82
references.pmid: 13342361
references.citation: Nat Chem Biol. 2005 Dec;1(7):377-82
references.pmid: 16370373
references.citation: Nat Med. 2006 Mar;12(3):304-6
references.pmid: 16501570
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3782-7
references.pmid: 11891296