2. Academic Validation
  3. Identification of Novel Mast Cell Activators Using Cell-Based High-Throughput Screening

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

  • SLAS Discov. 2019 Jul;24(6):628-640. doi: 10.1177/2472555219834699.
Hae Woong Choi 1,  Cliburn Chan 2,  Ivo D Shterev 3 4,  Heather E Lynch 3 4 5,  Taylor J Robinette 5,  Brandi T Johnson-Weaver 1,  Jianling Shi 1,  Gregory D Sempowski 1 3 4 5,  So Young Kim 6,  John K Dickson 7,  David M Gooden 8,  Soman N Abraham 1 9 10 11,  Herman F Staats 1 4 10
Affiliations

Affiliations

  • 1 1 Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • 2 2 Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
  • 3 3 Duke Regional Biocontainment Laboratory, Duke University School of Medicine, Durham, NC, USA.
  • 4 4 Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
  • 5 5 Departments of Medicine, Duke University School of Medicine, Durham, NC, USA.
  • 6 6 Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
  • 7 7 AptaChem Consulting LLC, Apex, NC, USA.
  • 8 8 Department of Chemistry, Duke University, Durham, NC, USA.
  • 9 9 Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC, USA.
  • 10 10 Department of Immunology, Duke University Medical Center, Durham, NC, USA.
  • 11 11 Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore.
PMID: 30917061 DOI: 10.1177/2472555219834699
Abstract

Mast cells (MCs) are known to regulate innate and adaptive immunity. MC activators have recently been described as safe and effective vaccine adjuvants. Many currently known MC activators are inadequate for in vivo applications, however, and research on identifying novel MC activators is limited. In this study, we identified novel MC activators by using high-throughput screening (HTS) assays using approximately 55,000 small molecules. Data sets obtained by the primary HTS assays were statistically evaluated using quality control rules and the B-score calculation, and compounds with B-scores of >3.0 were chosen as mast cell activators (hits). These hits were re-evaluated with secondary and tertiary HTS assays, followed by further statistical analysis. From these hits, we selected 15 compounds that caused degranulation in murine and human MCs, with potential for flexible chemical modification for further study. Among these 15 compounds, ST101036, ST029248, and ST026567 exhibited higher degranulation potency than Other hit compounds in both human and mouse MCs. In addition, the 15 compounds identified promote de novo synthesis of cytokines and induce the release of eicosanoids from human and mouse MCs. HTS enabled us to identify small-molecule MC activators with unique properties that may be useful as vaccine adjuvants.

Keywords

degranulation; high-throughput screening; mast cell; mast cell activator.

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