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Antimicrobial Agents and Chemotherapy, May 2004, p. 1495-1502, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1495-1502.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Efficacy of Novel Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 against Human Parainfluenza Viruses In Vitro and In Vivo

Irina V. Alymova,1 Garry Taylor,2 Toru Takimoto,1 Tsu-Hsing Lin,3 Pooran Chand,3 Y. Sudhakara Babu,3 Chenghong Li,4 Xiaoping Xiong,4 and Allen Portner1*

Departments of Infectious Diseases,1 Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794,4 Center for Biomolecular Science, University of St. Andrews, St. Andrews, Fife KY16 9ST, Scotland,2 BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 352443

Received 31 July 2003/ Returned for modification 28 October 2003/ Accepted 8 January 2004

Human parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK2 cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 µM in HA inhibition assays and from 0.02 to 20 µM in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 µM. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of parainfluenza virus HN and may limit parainfluenza virus infections in humans.

* Corresponding author. Mailing address: Department of Infectious Diseases, Mail Stop 330, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3408. Fax: (901) 523-2622. E-mail: Allen.Portner{at}stjude.org.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1495-1502, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1495-1502.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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