Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors.
A series of eight antiviral compounds complexed with human rhinovirus 14 (HRV-14) were previously shown to displace segments of polypeptide chains in the floor of the "canyon" by as much as 0.45 nm in C-alpha positions from the native conformation (J. Badger, I. Minor, M. J. Kremer, M. A. Oliveira, T. J. Smith, J. P. Griffith, D. M. A. Guerin, S. Krishnaswamy, M. Luo, M. G. Rossman, M. A. McKinlay, G. D. Diana, F. J. Dutko, M. Fancher, R. R. Rueckert, and B. A. Heinz, Proc. Natl. Acad. Sci. USA 85:3304-3308, 1988). Because the canyon is thought to serve as the viral receptor-binding site (M. G. Rossmann, E. Arnold, J. W. Erickson, E. A. Frankenberger, J. P. Griffith, H. J. Hecht, J. E. Johnson, G. Kamer, M. Luo, A. G. Mosser, R. R. Rueckert, B. Sherry, and G. Vriend, Nature [London] 317:145-153, 1985; M. G. Rossmann and R. R. Rueckert, Microbiol. Sci. 4:206-214, 1987), these compounds were assessed for their ability to block adsorption of HRV-14 to HeLa cell membrane receptors. In parallel experiments, the compounds were assessed directly for antiviral activity in an in vitro plaque reduction assay in intact HeLa cells. All eight compounds blocked the adsorption of 50% of HRV-14 at approximately the same concentration required to reduce the number of visible plaques by 50% (MIC). A structurally related compound which was inactive in the plaque reduction assay had no effect on HRV-14 binding. A drug-resistant mutant of HRV-14 (Leu-1188), which was less sensitive to the eight compounds in plaque reduction assays was similarly less sensitive in the adsorption assay. We propose that the conformational changes in the floor of the HRV-14 canyon induced by these compounds substantially decrease adsorption of the virion to its receptor. These results provide further evidence for the role of the HRV canyon in receptor binding.
Pevear
D C
DC
Department of Virology and Oncopharmacology, Sterling Research Group, Rensselaer, New York 12144.
Fancher
M J
MJ
Felock
P J
PJ
Rossmann
M G
MG
Miller
M S
MS
Diana
G
G
Treasurywala
A M
AM
McKinlay
M A
MA
Dutko
F J
FJ
D000327:Adsorption; D000998:Antiviral Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D011991:Receptors, Virus / Q000378:metabolism*; D012229:Rhinovirus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D000998:Antiviral Agents; D011991:Receptors, Virus; D014764:Viral Proteins