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1.
Vaccine ; 11(12): 1185-7, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8256499

RESUMO

Balb/c mice were immunized with 2 x 2 micrograms of purified recombinant secreted haemagglutinin, derived from the A/Victoria/3/75 (H3N2) virus. In the first immunization, Ribi adjuvant was used, while for the booster injection a monophosphoryl lipid A/muramyl dipeptide combination was chosen. Mice immunized in this way were 90-100% protected against a challenge with 20 LD50 of mouse-adapted, homologous virus (strain X47). Bromelain-solubilized haemagglutinin gave only 70% protection under comparable conditions.


Assuntos
Hemaglutininas Virais/uso terapêutico , Vírus da Influenza A/imunologia , Vacinas contra Influenza/uso terapêutico , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas Sintéticas/uso terapêutico , Animais , DNA Viral/genética , Hemaglutininas Virais/genética , Hemaglutininas Virais/fisiologia , Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Sintéticas/genética
2.
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
3.
J Biol Chem ; 266(35): 23660-9, 1991 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-1748643

RESUMO

Infection by influenza virus is initiated by a cellular adhesion event that is mediated by the viral protein, hemagglutinin, which is exposed on the surface of the virion. Hemagglutinin recognizes and binds to cell surface sialic acid residues. Although each individual ligand binding interaction is weak, the high affinity of influenza virus for cells that bear sialic acid residues is thought to result from a multivalent attachment process involving many similar recognition events. To evaluate such binding we have synthesized three series of compounds, each containing two sialic acid residues separated by spacers of different length, and have tested them as ligands for influenza hemagglutinin. No increased binding to the bromelain-released hemagglutinin ectodomain was seen for any of the bivalent compounds as determined by 1H NMR titration. In contrast, however, a spacer length between sialic acid residues of approximately 55 A sharply increases the binding of these bidentate species to whole virus as determined by hemagglutination inhibition assays. The most effective compound containing glycines in the linking chain displayed 100-fold increased affinity for whole virus over the paradigm monovalent ligand, Neu5Ac alpha 2Me.


Assuntos
Eritrócitos/fisiologia , Hemaglutinação , Hemaglutininas Virais/fisiologia , Orthomyxoviridae/fisiologia , Ácidos Siálicos/metabolismo , Animais , Configuração de Carboidratos , Sequência de Carboidratos , Galinhas , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Ligantes , Luz , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Estrutura Molecular , Espalhamento de Radiação , Ácidos Siálicos/síntese química
4.
J Gen Virol ; 69 ( Pt 11): 2785-95, 1988 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3183628

RESUMO

At the pH required to trigger the membrane fusion activity of the influenza virus haemagglutinin (HA) the soluble ectodomain of the molecule, BHA, which is released from virus by bromelain digestion, aggregates into rosettes. Analyses of soluble proteolytic fragments derived from the rosettes indicated that aggregation is mediated by association of the conserved hydrophobic amino-terminal region of BHA2, the smaller glycopolypeptide component of each BHA subunit. Further analyses of the structure of the soluble fragments and of HA in its low pH conformation by electron microscopy, spectroscopy and in crosslinking experiments showed that, although the membrane distal globular domains lose their trimer structure at the pH of fusion, the central fibrous stem of the molecule remains trimeric and assumes a more stable conformation. The increase in length of BHA2 at low pH observed microscopically appears to result from movement of the amino-terminal region to the membrane proximal end of the molecule and in virus incubated at low pH the amino terminus may insert into the virus membrane. The consequences of these possibilities for the mechanism of membrane fusion are discussed.


Assuntos
Hemaglutininas Virais/fisiologia , Vírus da Influenza A/ultraestrutura , Fusão de Membrana , Orthomyxoviridae/fisiologia , Bromelaínas/farmacologia , Eletroforese em Gel de Poliacrilamida , Concentração de Íons de Hidrogênio , Substâncias Macromoleculares , Microscopia Eletrônica
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