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Clinical and Vaccine Immunology, November 2009, p. 1654-1659, Vol. 16, No. 11
1071-412X/09/$08.00+0     doi:10.1128/CVI.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye{triangledown}

Alla Musiyenko,1 Lucia Correa,2 Nicholas Stock,2 John H. Hutchinson,2 Daniel S. Lorrain,2 Gretchen Bain,2 Jilly F. Evans,2 and Sailen Barik1*

Department of Biochemistry and Molecular Biology (MSB 2370), University of South Alabama, College of Medicine, 307 University Blvd., Mobile, Alabama 36688-0002,1 Amira Pharmaceuticals, 9535 Waples Street, Ste. 100, San Diego, California 921212

Received 29 May 2009/ Returned for modification 28 July 2009/ Accepted 2 September 2009

Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology (MSB 2370), University of South Alabama, College of Medicine, 307 University Blvd., Mobile, AL 36688-0002. Phone: (251) 460-6840. Fax: (251) 460-6850. E-mail: sbarik{at}jaguar1.usouthal.edu

{triangledown} Published ahead of print on 16 September 2009.

Clinical and Vaccine Immunology, November 2009, p. 1654-1659, Vol. 16, No. 11
1071-412X/09/$08.00+0     doi:10.1128/CVI.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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