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Structural Evaluations of a Selective Human STINGA230 Agonist and Its Use in Macrophage Immunotherapies.
Tang, Zhichao; Zhao, Junxing; Li, Ying; Tomer, Shallu; Selvaraju, Manikandan; Tien, Nicholas; Sun, Diyun; Johnson, David K; Zhen, Anjie; Li, Pingwei; Wang, Jingxin.
Afiliação
  • Tang Z; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
  • Zhao J; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
  • Li Y; Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • Tomer S; Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States.
  • Selvaraju M; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
  • Tien N; Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States.
  • Sun D; Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • Johnson DK; Computation Chemical Biology Core and Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas 66047, United States.
  • Zhen A; Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States.
  • Li P; Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • Wang J; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
ACS Med Chem Lett ; 15(5): 653-658, 2024 May 09.
Article em En | MEDLINE | ID: mdl-38746895
ABSTRACT
Previously we identified a non-nucleotide agonist BDW568 that selectively activates the human STINGA230 allele. Here, we further characterized the mechanism of BDW568 and highlighted its potential use for selectively controlling the activation of engineered macrophages that constitutively express STINGA230 as a genetic adjuvant. We obtained the crystal structure of the C-terminal domain of STINGA230 complexed with BDW-OH (active metabolite) at 1.95 Å resolution. Structure-activity relationship studies revealed that all three heterocycles in BDW568 and the S-acetate side chain are critical for retaining activity. We demonstrated that BDW568 could robustly activate type I interferon signaling in purified human primary macrophages that were transduced with lentivirus expressing STINGA230. In contrast, BDW568 could not stimulate innate immune responses in human primary peripheral blood mononuclear cells in healthy donors in the absence of a STINGA230 allele. This high STING variant specificity suggested a promising application of STINGA230 agonists in macrophage-based therapeutic approaches.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2024 Tipo de documento: Article