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J. Biol. Chem., Vol. 276, Issue 42, 38988-38994, October 19, 2001

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Antiviral Activity and Structural Characteristics of the Nonglycosylated Central Subdomain of Human Respiratory Syncytial Virus Attachment (G) Glycoprotein^*

Jeffrey J. Gorman, Jennifer L. McKimm-Breschkin^§, Raymond S. Norton^¶, and Kevin J. Barnham

From the Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria 3052, Australia

Segments of the cystine noose-containing nonglycosylated central subdomain, residues 149-197, of the attachment (G) glycoprotein of human respiratory syncytial virus (HRSV) have been assessed for impact on the cytopathic effect (CPE) of respiratory syncytial virus (RSV). N-acetyl residues 149-197-amide (G149-197), G149-189, and G149-177 of the A2 strain of HRSV protected 50% of human epithelial HEp-2 cells from the CPE of the A2 strain at concentrations (IC₅₀) between 5 and 80 µM. Cystine noose-containing peptides G171-197 and G173-197 did not inhibit the CPE even at concentrations above 150 µM. Systematic C- and N-terminal truncations from G149-189 and G149-177 and alanine substitutions within G154-177 demonstrated that residues 166-170 (EVFNF), within a sequence that is conserved in HRSV strains, were critical for inhibition. Concordantly, G154-177 of bovine RSV and of an antibody escape mutant of HRSV with residues 166-170 of QTLPY and EVSNP, respectively, were not inhibitory. Surprisingly, a variant of G154-177 with an E166A substitution had an IC₅₀ of 750 nM. NMR analysis demonstrated that G149-177 adopted a well-defined conformation in solution, clustered around F168 and F170. G154-170, particularly EVFNF, may be important in binding of RSV to host cells. These findings constitute a promising platform for the development of antiviral agents for RSV.

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