STRUCTURE-BASED IDENTIFICATION OF AN INDUCER OF THE LOW-PH CONFORMATIONAL CHANGE IN THE INFLUENZA-VIRUS HEMAGGLUTININ - IRREVERSIBLE INHIBITION OF INFECTIVITY

Citation
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
Citations number
59
Categorie Soggetti
Virology
Journal title
ISSN journal
0022538X
Volume
71
Issue
11
Year of publication
1997
Pages
8808 - 8820
Database
ISI
SICI code
0022-538X(1997)71:11<8808:SIOAIO>2.0.ZU;2-0
Abstract
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.