期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 21, 页码 4931-4938出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.09.039
关键词
Toll-like receptor 4; MD-2; 4-Aminoquinazolines; NF-kappa B activation; Innate immune response
资金
- National Institute of Allergy and Infectious Diseases from the National Institutes of Health [HHSN272200900034C]
The Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-kappa B activation. A human cell-based high throughput screen (HTS) revealed substituted 4-aminoquinazolines to be small molecular weight activators of NF-kappa B. The most potent hit compound predominantly stimulated through the human TLR4/MD2 complex, and had less activity with the mouse TLR4/MD2. There was no activity with other TLRs and the TLR4 activation was MD-2 dependent and CD14 independent. Synthetic modifications of the quinazoline scaffold at the 2 and 4 positions revealed trends in structure-activity relationships with respect to TLR dependent production of the NF-kappa B associated cytokine IL-8 in human peripheral blood mononuclear cells, as well as IL-6 in mouse antigen presenting cells. Furthermore, the hit compound in this series also activated the interferon signaling pathway resulting in type I interferon production. Substitution at the O-phenyl moiety with groups such as bromine, chlorine and methyl resulted in enhanced immunological activity. Computational studies indicated that the 4-aminoquinazoline compounds bind primarily to human MD-2 in the TLR4/MD-2 complex. These small molecules, which preferentially stimulate human rather than mouse innate immune cells, may be useful as adjuvants or immunotherapeutic agents. (C) 2014 The Authors. Published by Elsevier Ltd.
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