Small-molecule costimulatory blockade: organic dye inhibitors of the CD40-CD154 interaction.
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.
Margolles-Clark
Emilio
E
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Umland
Oliver
O
Kenyon
Norma S
NS
Ricordi
Camillo
C
Buchwald
Peter
P
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
D019013:CD40 Antigens; D004396:Coloring Agents; D007166:Immunosuppressive Agents; D023201:CD40 Ligand
Biochem Pharmacol. 2009 Apr 1;77(7):1236-45
19283894
Protein Eng Des Sel. 2007 Mar;20(3):133-41
17307885
J Pept Res. 2005 Jun;65(6):591-604
15885118
Annu Rev Immunol. 2004;22:307-28
15032580
J Biomol Screen. 2008 Jun;13(5):415-23
18490662
Cell Mol Life Sci. 2001 Jan;58(1):4-43
11229815
Clin Exp Immunol. 1981 Feb;43(2):260-9
7273480
J Clin Invest. 2004 Oct;114(7):979-87
15467837
Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8132-7
10393960
Immunol Rev. 2009 May;229(1):271-93
19426228
Mol Immunol. 2008 Feb;45(4):937-44
17959249
J Comput Aided Mol Des. 2006 Feb;20(2):109-30
16622794
Mod Rheumatol. 2005;15(6):423-6
17029106
Curr Top Med Chem. 2007;7(10):928-42
17508924
Nature. 2007 Dec 13;450(7172):1001-9
18075579
Infect Immun. 1999 Nov;67(11):5573-8
10531202
Nat Rev Immunol. 2004 Apr;4(4):259-68
15057784
Diabetes. 2006 Sep;55(9):2437-45
16936191
Nat Rev Drug Discov. 2004 Apr;3(4):301-17
15060526
J Physiol Pharmacol. 1993 Sep;44(3):213-32
8241524
J Toxicol Sci. 2008 Feb;33(1):71-83
18303186
J Periodontal Res. 1999 May;34(4):203-13
10444744
J Med Chem. 2002 Apr 11;45(8):1712-22
11931626
J Biol Chem. 1998 Sep 18;273(38):24603-9
9733755
Clin Microbiol Rev. 2005 Jul;18(3):521-40
16020688
J Mol Med (Berl). 2009 Feb;87(2):181-97
18985310
Nat Med. 2000 Feb;6(2):114
10655072
Nat Protoc. 2006;1(2):550-3
17191086
Biochemistry. 2001 Nov 13;40(45):13520-8
11695899
Br J Haematol. 1956 Jul;2(3):276-82
13342361
Nat Chem Biol. 2005 Dec;1(7):377-82
16370373
Nat Med. 2006 Mar;12(3):304-6
16501570
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3782-7
11891296