Peptides derived from heptad repeat regions adjacent to the fusion peptide
and transmembrane domains of many viral fusion proteins form stable helical
bundles and inhibit fusion specifically. Paramyxovirus SV5 fusion (F) prot
ein-mediated fusion and its inhibition by the peptides N-1 and C-1 were ana
lyzed. The temperature dependence of fusion by F suggests that thermal ener
gy, destabilizing praline residues and receptor binding by the hemagglutini
n-neuraminidase (HN) protein collectively contribute to F activation from a
metastable native state. F-mediated fusion was reversibly arrested by low
temperature or membrane-incorporated lipids, and the resulting F intermedia
tes were characterized. N-1 inhibited an earlier F intermediate than C-1. C
o-expression of HN with F lowered the temperature required to attain the N-
1-inhibited intermediate, consistent with HN binding to its receptor stimul
ating a conformational change in F. C-1 bound and inhibited an intermediate
of F that could be detected until a point directly preceding membrane merg
er. The data are consistent with C-1 binding a pre-hairpin intermediate of
F and with helical bundle formation being coupled directly to membrane fusi
on.