Abstract:
:Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Chen L,Jin Y,Chen H,Sun C,Fu W,Zheng L,Lu M,Chen P,Chen G,Zhang Y,Liu Z,Wang Y,Song Z,Liang Gdoi
10.1016/j.ejmech.2017.11.066subject
Has Abstractpub_date
2018-01-01 00:00:00pages
361-375eissn
0223-5234issn
1768-3254pii
S0223-5234(17)30969-8journal_volume
143pub_type
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