期刊
ACS INFECTIOUS DISEASES
卷 8, 期 6, 页码 1171-1178出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.2c00125
关键词
conjugates; docking experiments; inflammation; lipopolysaccharide; Toll-like receptors; antagonist
资金
- National Institute of General Medical Sciences [GM111835]
This study reports the development of a new Lipid-A analogue lacking a disaccharide core but still exhibiting potent antagonistic activity against LPS-induced inflammation. Computational, synthetic, and biological studies revealed new structural determinants of these simplified analogues.
Sepsis is a serious medical condition characterized by bacterial infection and a subsequent massive systemic inflammatory response. In an effort to identify compounds that block lipopolysaccharide (LPS)-induced inflammation reported herein is the development of simple Lipid-A analogues that lack a disaccharide core yet still possess potent antagonistic activity against LPS. The structure of the new lead compound was developed based on predictive computational experiments. LPS antagonism by the lead compound was not straightforward, and a biphasic effect was observed suggesting a possibility of more than one binding site. An IC50 value of 13 nM for the new compound was determined for the possible high affinity site. The combination of computational, synthetic, and biological studies revealed new structural determinants of these simplified analogues. It is expected that the acquired information will aid future design of LPS targeting glycopharmaceuticals.
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