Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction.
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 (microM) 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 (DeltaG(0)/nonhydrogen atom = 0.8 kJ/N(nHa)) approaching the average of known promising small-molecule PPI inhibitors (approximately 1.0 kJ/N(nHa)). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-alpha 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.
Buchwald
Peter
P
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA. pbuchwald@med.miami.edu
Margolles-Clark
Emilio
E
Kenyon
Norma S
NS
Ricordi
Camillo
C
D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000737:chemistry / Q000378:metabolism*; D023201:CD40 Ligand / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism; D013498:Suramin / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism
D019013:CD40 Antigens; D004396:Coloring Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D013498:Suramin