Lowering of trichosanthin immunogenicity by site-specific coupling to dextran
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摘要Trichosanthin is a type I ribosome-inactivating protein possessing a broad spectrum of biological and pharmacological activities. Therapeutic use of this compound is hampered by its immunogenicity. It was shown earlier that coupling of dextran to trichosanthin can increase plasma half-life and reduce antigenicity. However, the site where dextran attaches to trichosanthin cannot be controlled; ideally, it should be at or near the antigenic determinant. The present study attempted to couple dextran to trichosanthin at a potential antigenic site. By site-directed mutagenesis, two sites, R29 and K173, were replaced by cysteine, and dextran was coupled to the newly created cysteine residues. The dextran-trichosanthin complex retained 50% of abortifacient activity and had a mean residence time in rats 27-fold longer than natural trichosanthin. Acute hypersensitivity reaction in guinea pigs was reduced greatly after coupling of K173C (a trichosanthin mutant with lysine-173 replaced by cysteine) to dextran. Compared with natural trichosanthin, dextran-K173C had a decrease in IgG and IgE response, whereas the coupling of R29C (a trichosanthin mutant with arginine-29 replaced by cysteine) to dextran did not show significant reduction of immunogenicity. This suggests that K173 but not R29 is located at or near an antigenic determinant. This study has demonstrated an alternative approach for mapping of antigenic determinants. The information obtained is also useful in producing an improved trichosanthin derivative for therapeutic use. BIOCHEM PHARMACOL 57;8:927-934, 1999. (C) 1999 Elsevier Science Inc.
著者Chan WL, Shaw PC, Li XB, Xu QF, He XH, Tam SC
期刊名稱Biochemical Pharmacology
出版年份1999
月份4
日期15
卷號57
期次8
出版社PERGAMON-ELSEVIER SCIENCE LTD
頁次927 - 934
國際標準期刊號0006-2952
電子國際標準期刊號1873-2968
語言英式英語
關鍵詞dextran modification; IgE; immunogenicity; ribosome-inactivating protein; site-directed mutagenesis; trichosanthin
Web of Science 學科類別Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

上次更新時間 2020-14-10 於 01:39