Effective and specific inhibition of the CD40-CD154 costimulatory interaction by a naphthalenesulphonic acid derivative

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Costimulatory interactions are important regulators of T-cell activation and, hence, promising therapeutic targets in autoimmune diseases as well as in transplant recipients. Following our recent identification of the first small-molecule inhibitors of the CD40-CD154 costimulatory protein-protein interaction (J Mol Med 87, 2009, 1133), we continued our search within the chemical space of organic dyes, and we now report the identification of the naphthalenesulphonic acid derivative mordant brown 1 as a more active, more effective, and more specific inhibitor. Flow cytometry experiments confirmed its ability to concentration-dependently inhibit the CD154(CD40L)-induced cellular responses in human THP-1 cells at concentrations well below cytotoxic levels. Binding experiments showed that it not only inhibits the CD40-CD154 interaction with sub-micromolar activity, but it also has considerably more than 100-fold selectivity toward this interaction even when compared to other members of the tumor necrosis factor superfamily pairs such as TNF-R1-TNF-α, BAFF-R(CD268)-BAFF(CD257/BLys), OX40(CD134)-OX40L(CD252), RANK(CD265)- RANKL(CD254/TRANCE), or 4-1BB(CD137)-4-1BBL. There is now sufficient structure-activity relationship information to serve as the basis of a drug discovery initiative targeting this important costimulatory interaction.

Original languageEnglish
Pages (from-to)305-313
Number of pages9
JournalChemical Biology and Drug Design
Volume76
Issue number4
DOIs
StatePublished - Oct 1 2010

Fingerprint

Derivatives
Transplants
CD40 Ligand
Acids
T-cells
Flow cytometry
Drug Discovery
Structure-Activity Relationship
Autoimmune Diseases
Flow Cytometry
Proteins
Coloring Agents
Tumor Necrosis Factor-alpha
Experiments
Chemical activation
T-Lymphocytes
Molecules
Therapeutics
mordant brown 1
Transplant Recipients

Keywords

  • BAFF
  • CD40L
  • costimulatory blockade
  • immune suppression
  • OX40
  • protein-protein interaction
  • THP-1 cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

@article{674506ce11fa41a0bc3bdb80fbdf7f73,
title = "Effective and specific inhibition of the CD40-CD154 costimulatory interaction by a naphthalenesulphonic acid derivative",
abstract = "Costimulatory interactions are important regulators of T-cell activation and, hence, promising therapeutic targets in autoimmune diseases as well as in transplant recipients. Following our recent identification of the first small-molecule inhibitors of the CD40-CD154 costimulatory protein-protein interaction (J Mol Med 87, 2009, 1133), we continued our search within the chemical space of organic dyes, and we now report the identification of the naphthalenesulphonic acid derivative mordant brown 1 as a more active, more effective, and more specific inhibitor. Flow cytometry experiments confirmed its ability to concentration-dependently inhibit the CD154(CD40L)-induced cellular responses in human THP-1 cells at concentrations well below cytotoxic levels. Binding experiments showed that it not only inhibits the CD40-CD154 interaction with sub-micromolar activity, but it also has considerably more than 100-fold selectivity toward this interaction even when compared to other members of the tumor necrosis factor superfamily pairs such as TNF-R1-TNF-α, BAFF-R(CD268)-BAFF(CD257/BLys), OX40(CD134)-OX40L(CD252), RANK(CD265)- RANKL(CD254/TRANCE), or 4-1BB(CD137)-4-1BBL. There is now sufficient structure-activity relationship information to serve as the basis of a drug discovery initiative targeting this important costimulatory interaction.",
keywords = "BAFF, CD40L, costimulatory blockade, immune suppression, OX40, protein-protein interaction, THP-1 cells",
author = "Emilio Margolles-Clark and Kenyon, {Norma S} and Camillo Ricordi and Peter Buchwald",
year = "2010",
month = "10",
day = "1",
doi = "10.1111/j.1747-0285.2010.01014.x",
language = "English",
volume = "76",
pages = "305--313",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "4",

}

TY - JOUR

T1 - Effective and specific inhibition of the CD40-CD154 costimulatory interaction by a naphthalenesulphonic acid derivative

AU - Margolles-Clark, Emilio

AU - Kenyon, Norma S

AU - Ricordi, Camillo

AU - Buchwald, Peter

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Costimulatory interactions are important regulators of T-cell activation and, hence, promising therapeutic targets in autoimmune diseases as well as in transplant recipients. Following our recent identification of the first small-molecule inhibitors of the CD40-CD154 costimulatory protein-protein interaction (J Mol Med 87, 2009, 1133), we continued our search within the chemical space of organic dyes, and we now report the identification of the naphthalenesulphonic acid derivative mordant brown 1 as a more active, more effective, and more specific inhibitor. Flow cytometry experiments confirmed its ability to concentration-dependently inhibit the CD154(CD40L)-induced cellular responses in human THP-1 cells at concentrations well below cytotoxic levels. Binding experiments showed that it not only inhibits the CD40-CD154 interaction with sub-micromolar activity, but it also has considerably more than 100-fold selectivity toward this interaction even when compared to other members of the tumor necrosis factor superfamily pairs such as TNF-R1-TNF-α, BAFF-R(CD268)-BAFF(CD257/BLys), OX40(CD134)-OX40L(CD252), RANK(CD265)- RANKL(CD254/TRANCE), or 4-1BB(CD137)-4-1BBL. There is now sufficient structure-activity relationship information to serve as the basis of a drug discovery initiative targeting this important costimulatory interaction.

AB - Costimulatory interactions are important regulators of T-cell activation and, hence, promising therapeutic targets in autoimmune diseases as well as in transplant recipients. Following our recent identification of the first small-molecule inhibitors of the CD40-CD154 costimulatory protein-protein interaction (J Mol Med 87, 2009, 1133), we continued our search within the chemical space of organic dyes, and we now report the identification of the naphthalenesulphonic acid derivative mordant brown 1 as a more active, more effective, and more specific inhibitor. Flow cytometry experiments confirmed its ability to concentration-dependently inhibit the CD154(CD40L)-induced cellular responses in human THP-1 cells at concentrations well below cytotoxic levels. Binding experiments showed that it not only inhibits the CD40-CD154 interaction with sub-micromolar activity, but it also has considerably more than 100-fold selectivity toward this interaction even when compared to other members of the tumor necrosis factor superfamily pairs such as TNF-R1-TNF-α, BAFF-R(CD268)-BAFF(CD257/BLys), OX40(CD134)-OX40L(CD252), RANK(CD265)- RANKL(CD254/TRANCE), or 4-1BB(CD137)-4-1BBL. There is now sufficient structure-activity relationship information to serve as the basis of a drug discovery initiative targeting this important costimulatory interaction.

KW - BAFF

KW - CD40L

KW - costimulatory blockade

KW - immune suppression

KW - OX40

KW - protein-protein interaction

KW - THP-1 cells

UR - http://www.scopus.com/inward/record.url?scp=77956400879&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956400879&partnerID=8YFLogxK

U2 - 10.1111/j.1747-0285.2010.01014.x

DO - 10.1111/j.1747-0285.2010.01014.x

M3 - Article

C2 - 20636329

AN - SCOPUS:77956400879

VL - 76

SP - 305

EP - 313

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 4

ER -