Antiviral activity and structural characteristics of the nonglycosylated central subdomain of human respiratory syncytial virus attachment (G) glycoprotein
Jj. Gorman et al., Antiviral activity and structural characteristics of the nonglycosylated central subdomain of human respiratory syncytial virus attachment (G) glycoprotein, J BIOL CHEM, 276(42), 2001, pp. 38988-38994
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 effe
ct (CPE) of respiratory syncytial virus (RSV). N alpha -acetyl residues 149
-197-amide (G149-197), 6149-189, and 6149-177 of the A2 strain of HRSV prot
ected 50% of human epithelial HEp-2 cells from the CPE of the A2 strain at
concentrations (IC50) between 5 and 80 muM. Cystine noose-containing peptid
es G171-197 and G173-197 did not inhibit the CPE even at concentrations abo
ve 150 muM. Systematic C- and N-terminal truncations from 6149-189 and 6149
-177 and alanine substitutions within G154-177 demonstrated that residues 1
66-170 (EVFNF), within a sequence that is conserved in HRSV strains, were c
ritical for inhibition. Concordantly, G154-177 of bovine RSV and of an anti
body escape mutant of HRSV with residues 166-170 of QTLPY and EVSNP, respec
tively, were not inhibitory. Surprisingly, a variant of G154-177 with an E1
66A 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 deve
lopment of antiviral agents for RSV.