Rational design of potent domain antibody inhibitors of amyloid fibril assembly.
Proc Natl Acad Sci U S A
; 109(49): 19965-70, 2012 Dec 04.
Article
em En
| MEDLINE
| ID: mdl-23161913
ABSTRACT
Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer's and Huntington's diseases. However, near-stoichiometric antibody concentrations are typically required to completely inhibit protein aggregation. We posited that the molecular interactions mediating amyloid fibril formation could be harnessed to generate antibodies with potent antiaggregation. Here we report that grafting small amyloidogenic peptides (6-10 residues) into the complementarity-determining regions of a single-domain (V(H)) antibody yields potent domain antibody inhibitors of amyloid formation. Grafted AMyloid-Motif AntiBODIES (gammabodies) presenting hydrophobic peptides from Aß (Alzheimer's disease), α-Synuclein (Parkinson's disease), and islet amyloid polypeptide (type 2 diabetes) inhibit fibril assembly of each corresponding polypeptide at low substoichiometric concentrations (110 gammabodymonomer molar ratio). In contrast, sequence- and conformation-specific antibodies that were obtained via immunization are unable to prevent fibrillization at the same substoichiometric concentrations. Gammabodies prevent amyloid formation by converting monomers and/or fibrillar intermediates into small complexes that are unstructured and benign. We expect that our antibody design approach--which eliminates the need for immunization or screening to identify sequence-specific domain antibody inhibitors--can be readily extended to generate potent aggregation inhibitors of other amyloidogenic polypeptides linked to human disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Engenharia de Proteínas
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Peptídeos beta-Amiloides
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Alfa-Sinucleína
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
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Anticorpos de Domínio Único
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Amiloide
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article