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Biochemistry ; 32(12): 2967-78, 1993 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-8457561

RESUMO

Influenza hemagglutinin (HA) undergoes a conformational change that is required for viral entry. The rearrangement includes exposure of the fusion peptide, a hydrophobic segment buried in the trimer interface of the native protein. Since fusion peptide release triggers the membrane fusion event crucial for viral replication, inhibition of fusion peptide exposure should prevent infection. We reasoned that small molecules that bind to HA and stabilize its nonfusogenic conformation would block viral activity. A computer-assisted method was used to select putative HA ligands. One of the selected compounds, 4A,5,8,8A-tetrahydro-5,8-methano-1,4-naphthoquinone, prevented the conversion of X31 HA to a conformation recognized by alpha-fusion peptide antisera. Several derivatives of this compound, including both benzoquinones and hydroquinones, also showed inhibition. The most effective compounds tested have IC50S between 1 and 20 microM. Representative compounds also inhibited virus-induced syncytia formation, HA-mediated hemolysis, and viral infectivity in vitro. The inhibitors are attractive leads for the development of antiviral drugs and can serve as probes of the mechanism of the conformational change of HA.


Assuntos
Benzoquinonas/farmacologia , Hemaglutininas Virais/química , Hidroquinonas/farmacologia , Fusão de Membrana/fisiologia , Orthomyxoviridae/química , Benzoquinonas/metabolismo , Bromelaínas/metabolismo , Linhagem Celular , Simulação por Computador , Fluorescência , Hemaglutinação/efeitos dos fármacos , Hemaglutininas Virais/metabolismo , Hemaglutininas Virais/fisiologia , Hemólise , Concentração de Íons de Hidrogênio , Hidroquinonas/metabolismo , Cinética , Fusão de Membrana/efeitos dos fármacos , Modelos Moleculares , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Fragmentos de Peptídeos/metabolismo , Conformação Proteica/efeitos dos fármacos
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