Toward Selective Covalent Inactivation of Pathogenic Antibodies
| Autor: | Yukie Mitsuda, Hiroaki Taguchi, Sudhir Paul, Yasuhiro Nishiyama, Stephanie Planque, Yogesh Bangale, Sangeeta Karle, Gita Bhatia |
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| Rok vydání: | 2004 |
| Předmět: |
genetic structures
biology Stereochemistry Vasoactive intestinal peptide Cell Biology Biochemistry Phosphonate law.invention chemistry.chemical_compound Residue (chemistry) chemistry law Covalent bond Polyclonal antibodies Recombinant DNA biology.protein Peptide bond Molecular Biology Hapten hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Biological Chemistry. 279:7877-7883 |
| ISSN: | 0021-9258 |
| Popis: | We report the selective inactivation of proteolytic antibodies (Abs) to an autoantigen, the neuropeptide vasoactive intestinal peptide (VIP), by a covalently reactive analog (CRA) of VIP containing an electrophilic phosphonate diester at the Lys20 residue. The VIP-CRA was bound irreversibly by a monoclonal Ab that catalyzes the hydrolysis of VIP. The reaction with the VIP-CRA proceeded more rapidly than with a hapten CRA devoid of the VIP sequence. The covalent binding occurred preferentially at the light chain subunit of the Ab. Covalent VIP-CRA binding was inhibited by VIP devoid of the phosphonate diester group. These results indicate the importance of noncovalent VIP recognition in guiding Ab nucleophilic attack on the phosphonate group. Consistent with the covalent binding data, the VIP-CRA inhibited catalysis by the recombinant light chain of this Ab with potency greater than the hapten-CRA. Catalytic hydrolysis of VIP by a polyclonal VIPase autoantibody preparation that cleaves multiple peptide bonds located between residues 7 and 22 essentially was inhibited completely by the VIP-CRA, suggesting that the electrophilic phosphonate at Lys20 enjoys sufficient conformational freedom to react covalently with Abs that cleave different peptide bonds in VIP. These results suggest a novel route to antigen-specific covalent targeting of pathogenic Abs. |
| Databáze: | OpenAIRE |
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