Ž . International Immunopharmacology 1 2001 1211–1218 www.elsevier.comrlocaterintimp Primary immune system effects of the orally administered cyclopentane neuraminidase inhibitor RWJ-270201 in influenza virus-infected mice Robert W. Sidwell a, ) , Donald F. Smee a , Kevin W. Bailey a , Roger A. Burger b a Institute for AntiÕiral Research, Utah State UniÕersity, 5600 Old Main Hill, Logan, UT 84322-5600, USA b Miltenyi Biotech, 251 Auburn RaÕine Rd., Suite 208, Auburn, CA 95603, USA Received 21 November 2000; received in revised form 8 February 2001; accepted 12 February 2001 Abstract w x wŽ . Ž . x wŽ . x The cyclopentane derivative 1 S,2 S,3 R,4 R -3- 1 S -1- acetylamino -2-ethylbutyl -4- aminoiminomethyl amino -2-hy- Ž . droxy-cyclopentanecarboxylic acid RWJ-270201 has been previously reported to be a potent and selective inhibitor of influenza virus neuraminidase, and to inhibit infections with this virus in vitro, in mice, and in clinical challenge studies. The effect of oral gavage therapy of 100 mgrkgrday of RWJ-270201 administered twice daily for 5 days beginning 16 h prior to virus exposure, on various immune factors of importance in response to primary influenza infection was determined in Ž . mice infected with influenza ArShangdongr09r93 H3N2 virus. Spleens taken from the mice 2 h after termination of Ž . Ž . treatment were processed for cytotoxic T lymphocytes CTL and natural killer NK cell activity and for enumeration of macrophages, T, T-helper, T-suppressorrcytotoxic, and B cells. Saline-treated mice and normal mice were run in parallel. Treatment had no significant effect on any immune parameter. In a second experiment, mice infected with influenza Ž . ArNWSr33 H1N1 were treated similarly with RWJ-270201 beginning 4 h pre-virus exposure. Treatment prevented any deaths from occurring, and markedly lessened arterial oxygen decline, lung consolidation, and lung virus titers. The mice Ž . developed mean neutralizing antibody NA titers of 1:592, and six of seven rechallenged mice resisted rechallenge with the same virus, indicating the initial virus-inhibitory effect also did not prevent the animals from developing an adequate humoral immune response to the virus. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Influenza; RWJ-270201; Neuraminidase inhibitor; Natural killer cell; Cytotoxic T cell; Macrophage; Antiviral 1. Introduction It has been established that the influenza virus neuraminidase, expressed on the virion surface, is a wx key target for antiviral intervention 1 . The enzyme ) Corresponding author. Tel.: q 1-435-797-1902; fax: q 1-435- 797-3959. Ž . E-mail address: Rsidwell@cc.usu.edu R.W. Sidwell . is essential for influenza virus replication and infec- tivity, is required for elution of synthesized virions from host cells, and promotes movement of the virus w x through the mucus of the respiratory tract 1–4 . A recently described inhibitor of influenza virus neu- w x wŽ . Ž . raminidase, 1 S,2 S,3 R,4 R -3- 1 S -1- acetylamino - x wŽ . x 2-ethylbutyl -4- aminoiminomethyl amino -2-hydro- Ž .Ž xy-cyclopentanecarboxylic acid RWJ-270201 Fig. . 1 has potent in vitro activity against a broad spec- w x trum of influenza viruses 5,6 . It has also been 1567-5769r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. Ž . PII: S1567-5769 01 00058-3