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Antimicrobial Agents and Chemotherapy, November 1998, p. 2824-2829, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Suppression of Murine Endotoxin Response by E5531, a Novel Synthetic Lipid A Antagonist

Seiichi Kobayashi,1,* Tsutomu Kawata,1 Akifumi Kimura,1 Kaname Miyamoto,1 Koichi Katayama,1 Isao Yamatsu,1 Daniel P. Rossignol,2 William J. Christ,2,dagger and Yoshito Kishi2

Eisai Co., Ltd. Tsukuba Research Laboratories, Tsukuba, Japan,1 and Eisai Research Institute, Andover, Massachusetts2

Received 13 April 1998/Returned for modification 11 June 1998/Accepted 19 August 1998

As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A analogue, E5531, was designed and synthesized as an LPS antagonist, and its biological properties were examined in vitro and in vivo. In murine peritoneal macrophages, E5531 inhibited the release of tumor necrosis factor alpha (TNF-alpha ) by Escherichia coli LPS with a 50% inhibitory concentration (IC50) of 2.2 nM, while E5531 elicited no significant increases in TNF-alpha on its own. In support of a mechanism consistent with antagonism of binding to a cell surface receptor for LPS, E5531 inhibited equilibrium binding of radioiodinated LPS ([125I]2-(r-azidosalicylamido)-1, 3'-dithiopropionate-LPS) to mouse macrophages with an IC50 of 0.50 µM. E5531 inhibited LPS-induced increases in TNF-alpha in vivo when it was coinjected with LPS into C57BL/6 mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this model, the efficacy of E5531 was inversely correlated to the LPS challenge dose, consistent with a competitive antagonist-like mechanism of action. Blockade of the inflammatory response by E5531 could further be demonstrated in other in vivo models: E5531 protected BCG-primed mice from LPS-induced lethality in a dose-dependent manner and suppressed LPS-induced hepatic injury in Propionibacterium acnes-primed or galactosamine-sensitized mice. These results argue that the novel synthetic lipid A analogue E5531 can antagonize the action of LPS in in vitro and suppress the pathological effects of LPS in vivo in mice.

* Corresponding author. Mailing address: Eisai Co., Ltd, Tsukuba Research Laboratories for Drug Discovery, Biology unit I, 1-3, Tokodai 5-chome, Tsukuba, Ibaraki 300-26, Japan. Phone: 0298-47-5719. Fax: 0298-47-2037. E-mail: s1-kobayashi{at}eisai.co.jp.

dagger Present address: Eisai Merrimack Valley, Andover, MA 01810-1036.

Antimicrobial Agents and Chemotherapy, November 1998, p. 2824-2829, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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