title: Effect of site-directed PEGylation of trichosanthin on its biological activity, immunogenicity, and pharmacokinetics.
abstract: Trichosanthin (TCS) is a type I ribosome-inactivating protein (RIP) with multiple biological and pharmacological activities. It has been approved effective in the clinical treatment of AIDS and tumor, but its strong immunogenicity and short plasma half-life have limited the clinical administration. To reduce the immunogenicity and prolong the plasma half-life of this compound, three TCS muteins (M(1), M(2) and M(3)) and two PEGylated TCS muteins (PM(1) and PM(2)) were constructed by site-directed mutagenesis and PEGylation, respectively. Compared with the unmodified TCS, both PEGylated TCS showed a 3- to 4-fold decrease in immunogenicity, a 0.5- to 0.8-fold decrease in non-specific toxicity, and a 4.5- to 6-fold increase in plasma half-life. But there is a problem of activity reduction. The increased circulating half-life in vivo may compensate for the reduced activity. Together with the other benefits of PEGylation such as reduced immunogenicity and toxicity, it is worthwhile to further explore the potential application of the PEGylated TCS as a better therapeutic agent for AIDS and tumor.
authors.affiliation: Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University, Xi'an 710033, China.
authors.forename: Qunxing
authors.initials: Q
authors.lastname: An
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Lei
authors.forename: Ning
authors.initials: N
authors.lastname: Jia
authors.forename: Xianqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Yinlan
authors.initials: Y
authors.lastname: Bai
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Aijun
authors.initials: A
authors.lastname: Xia
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Sanhua
authors.initials: S
authors.lastname: Wei
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.forename: Ailing
authors.initials: A
authors.lastname: Fan
authors.forename: Shijie
authors.initials: S
authors.lastname: Mu
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D011092:Polyethylene Glycols / Q000737:chemistry*; D054788:Ribosome Inactivating Proteins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015978:Trichosanthin / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000972:Antineoplastic Agents, Phytogenic; D011092:Polyethylene Glycols; D015978:Trichosanthin; D054788:Ribosome Inactivating Proteins