Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury

Acute inflammatory
diseases, including acute lung injury and sepsis,
remain the most common life-threatening illness in intensive care
units worldwide. Cinnamamide has been incorporated in several synthetic
compounds with therapeutic potentials including anti-inflammatory
properties. However, the possible mechanism and direct molecular target
of cinnamamides for their anti-inflammatory effects were rarely investigated.
In this study, we synthesized a series of cinnamamides and evaluated
their anti-inflammatory activities. The most active compound, 2i, was found to block LPS-induced MD2/TLR4 pro-inflammatory
signaling activation in vitro and to attenuate LPS-caused sepsis and
acute lung injury in vivo. Mechanistically, we demonstrated that 2i exerts its anti-inflammatory effects by directly targeting
and binding MD2 in Arg90 and Tyr102 residues and inhibiting MD2/TLR4
complex formation. Taken together, this work presents a novel MD2
inhibitor, 2i, which has the potential to be developed
as a candidate for the treatment of sepsis, and provides a new lead
structure for the development of anti-inflammatory agents targeting
MD2.