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Journal of Virology, September 2008, p. 8400-8410, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00474-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Loss of the N-Linked Glycan at Residue 173 of Human Parainfluenza Virus Type 1 Hemagglutinin-Neuraminidase Exposes a Second Receptor-Binding Site{triangledown}

Irina V. Alymova,1 Garry Taylor,4 Vasiliy P. Mishin,1 Makiko Watanabe,1 K. Gopal Murti,2,{dagger} Kelli Boyd,3 Pooran Chand,5 Y. Sudhakara Babu,5 and Allen Portner1*

Departments of Infectious Diseases,1 Molecular Biotechnology,2 Animal Resources Center, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105-2794,3 Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland,4 BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, Alabama 352445

Received 4 March 2008/ Accepted 15 June 2008

BCX 2798 (4-azido-5-isobutyrylamino-2,3-didehydro-2,3,4,5-tetradeoxy-d-glycero-d-galacto-2-nonulopyranosic acid) effectively inhibited the activities of the hemagglutinin-neuraminidase (HN) of human parainfluenza viruses (hPIV) in vitro and protected mice from lethal infection with a recombinant Sendai virus whose HN was replaced with that of hPIV-1 (rSeV[hPIV-1HN]) (I. V. Alymova, G. Taylor, T. Takimoto, T. H. Lin., P. Chand, Y. S. Babu, C. Li, X. Xiong, and A. Portner, Antimicrob. Agents Chemother. 48:1495-1502, 2004). The ability of BCX 2798 to select drug-resistant variants in vivo was examined. A variant with an Asn-to-Ser mutation at residue 173 (N173S) in HN was recovered from mice after a second passage of rSeV(hPIV-1HN) in the presence of BCX 2798 (10 mg/kg of body weight daily). The N173S mutant remained sensitive to BCX 2798 in neuraminidase inhibition assays but was more than 10,000-fold less sensitive to the compound in hemagglutination inhibition tests than rSeV(hPIV-1HN). Its susceptibility to BCX 2798 in plaque reduction assays was reduced fivefold and did not differ from that of rSeV(hPIV-1HN) in mice. The N173S mutant failed to be efficiently eluted from erythrocytes and released from cells. It demonstrated reduced growth in cell culture and superior growth in mice. The results for gel electrophoresis analysis were consistent with the loss of the N-linked glycan at residue 173 in the mutant. Sequence and structural comparisons revealed that residue 173 on hPIV-1 HN is located close to the region of the second receptor-binding site identified in Newcastle disease virus HN. Our study suggests that the N-linked glycan at residue 173 masks a second receptor-binding site on hPIV-1 HN.

* 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

{triangledown} Published ahead of print on 25 June 2008.

{dagger} Retired.

Journal of Virology, September 2008, p. 8400-8410, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00474-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Watanabe, M., Mishin, V. P., Brown, S. A., Russell, C. J., Boyd, K., Babu, Y. S., Taylor, G., Xiong, X., Yan, X., Portner, A., Alymova, I. V. (2009). Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice. Antimicrob. Agents Chemother. 53: 3942-3951 [Abstract] [Full Text]  


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