生物工程学报 Chin J Biotech 2009, December 25; 25(12): 1852-1862 journals.im.ac.cn Chinese Journal of Biotechnology ISSN 1000-3061 cjb@im.ac.cn 2009 Institute of Microbiology, CAS & CSM, All rights reserved 综述 徐寒梅, 周长林, 郑珩, 吴梧桐, 210009 : 随着生物技术和现代药剂学研究的进展, 酶类药物的应用取得了快速发展, 已成为生物药物的一个重要门类 以下对治疗用酶的新品种 作用机理和新技术在治疗酶中的应用 酶作为药物靶点的应用等进行了回顾, 并对未来治疗酶的发展方向进行了讨论 : 治疗酶, 新品种, 作用机理, 新技术 Progress in the research of therapeutic enzyme Hanmei Xu, Changlin Zhou, Heng Zhen, and Wutong Wu Department of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China Abstract: With the development of the research on biotechnology and modern pharmacy, the application of enzyme drugs have grown rapidly and enzyme drugs have become an important branch of biopharmaceutics. In this article, some new varieties of therapeutic enzymes, enzyme targets, mechanisms and new technologies of application in therapeutic enzymes were reviewed, and the direction of development of therapeutic enzymes were discussed. Keywords: therapeutic enzyme, new varieties, mechanisms, new technologies,,,, 15 20, 100, : 1), β- α- ; 2) ; 3), ; 4), III (tpa) ; 5), ; 6),,,,,,,, Received: October 9, 2009; Accepted: November 6, 2009 Corresponding author: Wutong Wu. E-mail: wuwtong@cpu.edu.cn
: 1853 1 几种治疗酶的作用机理,,,, 1.1 治疗酶抗肿瘤的作用机制 - L-, L- L-, 3,, : ;, [1-2], -, cyc, cyc Apaf-1 Preocaspase-9, Caspase-9, ADP- (PARP), 1.1.2,,,,,,,,,,, 1.1.3 (Ribozyme, Rz) RNA, mrna, 20 80, Kruger [3] (RNA), RNA,, RNA, mrna, : 1) :, 1~2 mm,, (VEGF), VEGF VEGF (VEGFR), VEGF VEGFR, Tokunaga [4] VEGF189 MIA PaCa2,, VEGF, Ciafrè [5] VEGF mrna,
1854 ISSN1000-3061 CN11-1998/Q Chin J Biotech December 25, 2009 Vol.25 No.12, VEGF 56% Ribozyme Chiron Angiozyme (Ribozyme), Ⅱ, [6-9] 2) :,, ( ras ) ( Bcl-2 Bcl-xl) ( Bcl-2, C-myc ),,,, [10-12] 3) : (Multidrug resistance gene, MDR) (P-glycoprotien, P-gp),, ATP, ATP, P-gp,,,, P-gp, 1994 Kiehntopf [13-14] 6 4 GUC, MDR1 mrna, MDR-1-, MDR-1-, MDR1 mrna, MDR1 mrna MDR, P-gp 1.2 治疗酶溶解血栓的作用机制 tpa γapc 1, ( ), 3 :, ;, t-pa,,,, C(γh-APC),, 1.2.1 C C, C,, C TM( ),, C APC, APC S Ⅴ Ⅷ APC (PAI-1), PAI-1, APC
: 1855 1.2.2 (tpa) tpa, tpa, 2, tpa, 90 kd, tpa Arg561-Val562, -, N- Lys, C-, ( ), tpa, 1.3 胰酶制剂治疗慢性胰腺炎的作用机制, 图 1 凝血与纤溶过程 Fig. 1 Coagulation and fibrinolytic process. 图 2 t-pa 与纤溶过程 Fig. 2 t-pa and fibrinolytic process.
1856 ISSN1000-3061 CN11-1998/Q Chin J Biotech December 25, 2009 Vol.25 No.12 1.3.1 5~8 g,, (CP) 10 10%,, A D E K CP, >15 g/d, 1.3.2, CCK, CCK CP, CCK,, CCK, CCK,, CCK, CCK, CCK,, 2 新技术在治疗酶中的应用,, ;,,, 2.1 重组 DNA 技术应用于治疗酶,,,,, - BM,,,, 700 d I Ⅱ, DNA, [15],,,, 2.2 治疗酶的分子设计, (Site directed mutagenesis) (In vitro molecular directed evolution) 2.2.1 (Site-directed mutagenesis) (PCR) DNA, DNA,, (SBL),
: 1857 CMM K cat /K m, 22 [16] ; Ala L-, [17] 2.2.2,,,,, [18],,, [19], (MPEG),, X-, [20], - N- [17],, Cu(Phen) 2+ (Adipocyte lipid binding protein, ALBP), ALBP-Phen-Cu ( Ⅱ), 86%, 3 治疗酶的新品种和应用, : 1),, ; 2), ; 3),, PEG 3.1 研发中的溶栓酶 10, 3 (Urokinase) (Streptokinase),,,, ; (Tissue plasminogen activator, tpa) (Recombinant tissue plasminogen activator, rt-pa) (Scu-PA, u-pa ) tpa,,, ( 3 min),,, tpa,
1858 ISSN1000-3061 CN11-1998/Q Chin J Biotech December 25, 2009 Vol.25 No.12 : 3.1.1 tpa tpa,,, (Lanoteplase, npa), tpa, npa, ;, Novartis AG tpa (scu-pa) cdna Amediplase(K1K2Pu ), [21-22] 3.1.2 (Staphylokinase, Sak), sak 163, N 28 136 3, Sak42D SakΦC SakSTAR, 3 3,,, SakSTAR, Sak, rt-pa, Sak, Sak, : 1) 2, 73% IgG ; 2) Sak, 3 min Sak,, Sak Sak, [23-26] 3.1.3 (rhpro-uk),, (Urokinase, UK) ; 411, 5.0 10 4 5.4 10 4 12,, Lysl58-llel59 ; Argl56-Phel57 (Thromb-UK), tpa : 1),, tpa,, ; 2), [27] 3.1.4 (Nattokinase, NK; Subtilisin NAT, Subtilisin BSP) (Bacilius subtilis var. natto), (Subtilisin) 1987 200,,,,,,, [28-29] 3.1.5 (epa, lumbrokinase) (Earthworm plasminogen activator, EPA), (Lumbrokinase, LK), t-pa,, [30] 3.2 研发中的抗肿瘤酶,
: 1859 2,, L- [31-33] Wilm (Arginine deiminase, ADI, E.C. 3.5.3.6), (Ribonuclease, RNase) RNA, RNase, A(RNaseA) RNase(Onconase, ONC) RC-RNase RNase (BS-RNase) RNase(RNase I), RNA (Ribozyme, Rz) RNA, mrna, 3.3 开发中的其他酶类治疗药物,,,, : 1), 3 (MPS) : Aldurazymel( ) Aryplase( N-a -4- ); 2), Debrase MediWound,,, ⅡⅢ ; / Vibrilase( vibriolysin) Biomarin Pharm,, Ⅰ ; 3) Ⅰ [33] (Deoxyribonuclease I, DNase I), DNA, 5-3 -, DNaseⅠ, DNaseⅠ, DNaseⅠ, 4 酶作为药物靶点的研究, 500,,,,, - C, matriptase : matriptase, matriptase ( ) matriptase,,,
1860 ISSN1000-3061 CN11-1998/Q Chin J Biotech December 25, 2009 Vol.25 No.12, (camp)- 4(PDE4), (COPD),, - -ACP (Fab) Fab platensimycin [34-36] 5 治疗酶的增效作用, 5.1 治疗酶对抗生素的增效作用 1963 Seneca Peer [37], Seneca Peer :, 5.2 治疗酶对激素的增效作用 1969 Wohlman [38], 5 : 1) ; 2) ; 3) ; 4) ; 5),,, 5.3 治疗酶对细胞毒药物的增效作用,,, rhmnsod ADR,, [39], 6 结束语,,,, r-pa, DNA Fabry α- (α-galatosidaee) Gaucher s (Glulo cerebrosidaso) ;,,,,, (PEG) PEG-L, PEG ;,,, : SOD ;, FDA r-pa TNF-tPA t-pa,,,
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