Identification of Novel Mast Cell Activators Using Cell-Based High-Throughput Screening.

Area of Science:

• Immunology
• Pharmacology

Background:

• Mast cells (MCs) play a crucial role in regulating innate and adaptive immunity.
• Mast cell activators are recognized for their potential as vaccine adjuvants.
• Existing MC activators often have limitations for in vivo applications, necessitating the search for novel compounds.

Purpose of the Study:

• To identify novel small-molecule mast cell (MC) activators.
• To evaluate the potential of these novel compounds as vaccine adjuvants.

Main Methods:

• Utilized high-throughput screening (HTS) of approximately 55,000 small molecules.
• Employed rigorous statistical evaluation, including quality control rules and B-score calculations, to identify hit compounds.
• Conducted secondary and tertiary HTS assays to validate and re-evaluate selected compounds, including assessment of degranulation in murine and human MCs.

Main Results:

• Identified 15 small-molecule compounds that induce degranulation in both murine and human mast cells.
• Three compounds (ST101036, ST029248, ST026567) demonstrated superior degranulation potency.
• The identified compounds also promote de novo cytokine synthesis and eicosanoid release from MCs.

Conclusions:

• High-throughput screening is an effective method for discovering novel small-molecule mast cell activators.
• The identified compounds possess unique properties suitable for further development as vaccine adjuvants.
• These novel MC activators hold promise for improving vaccine efficacy and safety.