Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (mM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general.

Original languageEnglish
Pages (from-to)65-73
Number of pages9
JournalJournal of Molecular Recognition
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Coloring Agents
Proteins
Tumor Necrosis Factor-alpha
Suramin
Protein Binding
Cell Communication
B-Lymphocytes
Cell Proliferation
Staining and Labeling
Ligands

Keywords

  • Binding free energy
  • CD40 ligand
  • Costimulation
  • Immune suppression
  • Protein-protein interaction

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

@article{df8f547afd924db3829e97d57d600ce9,
title = "Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction",
abstract = "It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (mM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general.",
keywords = "Binding free energy, CD40 ligand, Costimulation, Immune suppression, Protein-protein interaction",
author = "Peter Buchwald and Emilio Margolles-Clark and Kenyon, {Norma S} and Camillo Ricordi",
year = "2010",
month = "1",
day = "1",
doi = "10.1002/jmr.969",
language = "English",
volume = "23",
pages = "65--73",
journal = "Journal of Molecular Recognition",
issn = "0952-3499",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction

AU - Buchwald, Peter

AU - Margolles-Clark, Emilio

AU - Kenyon, Norma S

AU - Ricordi, Camillo

PY - 2010/1/1

Y1 - 2010/1/1

N2 - It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (mM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general.

AB - It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (mM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (ΔG0/nonhydrogen atom 1/40.8 kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (~1.0 kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-a interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general.

KW - Binding free energy

KW - CD40 ligand

KW - Costimulation

KW - Immune suppression

KW - Protein-protein interaction

UR - http://www.scopus.com/inward/record.url?scp=73249129041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73249129041&partnerID=8YFLogxK

U2 - 10.1002/jmr.969

DO - 10.1002/jmr.969

M3 - Article

VL - 23

SP - 65

EP - 73

JO - Journal of Molecular Recognition

JF - Journal of Molecular Recognition

SN - 0952-3499

IS - 1

ER -