STRUCTURE-BASED IDENTIFICATION OF AN INDUCER OF THE LOW-PH CONFORMATIONAL CHANGE IN THE INFLUENZA-VIRUS HEMAGGLUTININ - IRREVERSIBLE INHIBITION OF INFECTIVITY
Lr. Hoffman et al., STRUCTURE-BASED IDENTIFICATION OF AN INDUCER OF THE LOW-PH CONFORMATIONAL CHANGE IN THE INFLUENZA-VIRUS HEMAGGLUTININ - IRREVERSIBLE INHIBITION OF INFECTIVITY, Journal of virology, 71(11), 1997, pp. 8808-8820
Past efforts to employ a structure-based approach to design an inhibit
or of the fusion-inducing conformational change in the influenza virus
hemagglutinin (HA) yielded a family of small benzoquinones and hydroq
uinones, The most potent of these, tert-butyl hydroquinone (TBHQ), inh
ibits both the conformational change in HA from strain X:31 influenza
virus and viral infectivity in tissue culture cells with 50% inhibitor
y concentrations in the micromolar range (D. L. Bodian, R. B. Yamasaki
, R. L. Buswell, J. F. Stearns, J. M. White, and I. D. Kuntz, Biochemi
stry 32:2967-2978, 1993). A new structure-based inhibitor design searc
h was begun which involved (i) the recently refined crystal structure
(2.1-Angstrom resolution) of the HA ectodomain, (ii) new insights into
the conformational change, and (iii) improvements in the molecular do
cking program, DOCK. As a result, we identified new inhibitors of HA-m
ediated membrane fusion. Like TBHQ, most of these molecules inhibit th
e conformational change, One of the new compounds, however, facilitate
s rather than inhibits the HA conformational change, Nonetheless, the
facilitator, diiodofluorescein, inhibits HA-mediated membrane fusion a
nd, irreversibly, infectivity. We further characterized the effects of
inhibitors from both searches on the conformational change and membra
ne fusion activity of HA as well as on viral infectivity. We also isol
ated and characterized several mutants resistant to each class of inhi
bitor. The implications of our results for HA-mediated membrane fusion
, anti-influenza virus therapy, and structure-based inhibitor design a
re discussed.