刘梦,于彭城,徐寒梅.蛋白多肽类药物长效化技术研究进展[J].药学进展,2019,43(03):209-216.
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蛋白多肽类药物长效化技术研究进展
刘梦于 彭城 徐寒梅
中国药科大学江苏省合成多肽药物发现与评价工程研究中心
摘要：近年来,蛋白多肽类药物因在治疗疾病方面具有显著的优点,普遍受到研究者的青睐;另一方面,蛋白多肽类药物半衰期一般较短,影响患者用药顺应性。结合蛋白多肽类药物药动学特点,总结蛋白多肽类药物长效化方法的研究进展,主要包括氨基酸替代、定点修饰突变、通过基因手段与其他蛋白融合、糖基化、环化、与聚合物缀合、钉合肽,以及新剂型开发等方法,希望能对药物研发工作者有所帮助。
关键词： 蛋白多肽类药物;药动学特点;长效化技术;
专辑： 医药卫生科技
专题： 药学
分类号： R96
文章目录
1 蛋白多肽类药物药动学特点
1.1 吸收
1.2 分布
1.3 代谢和消除
2 改善蛋白多肽类药物半衰期的方式
2.1 氨基酸替代
2.2 定点修饰突变
2.3 通过基因手段与其他蛋白融合
2.4 糖基化
2.5 环化
2.6 与聚合物缀合
2.6.1 PEG化学修饰
2.6.2 非结构化可生物降解蛋白缀合
2.6.3 PAS缀合
2.6.4 羟乙基化淀粉缀合
2.7 钉合肽
2.8 药物传递系统开发
3 结语
刘梦,于彭城,徐寒梅.蛋白多肽类药物长效化技术研究进展[J].药学进展,2019,43(03):209-216.
[ 作者介绍 ] 徐寒梅：中国药科大学教授，博士生导师，江苏省合成多肽药物发现与评价工程研究中心主任，国家药典委员会委员，中组部“万人计划”入选者。多年从事多肽药物的研究，带领团队自主设计合成了多个多肽药物、转让了 4 个 1 类多肽新药，有 2 个已经进入临床研究。近 5 年在国内外发表学术论文 80 余篇，SCI 论文 35 篇；主编及参编论著各 1 部，主编教材 1 部；申请发明专利及软件著作权共 35 项 ( 其中国际专利 5 项 )，获得授权 15 项。近年来，先后带领团队主持了：国家自然科学基金，国家“863”高科技发展计划，国家“十一五”、“十二五”、“十三五”重大新药创制科技重大专项多项，江苏省校企合作前瞻性研究等项目。2014 年获得江苏省医药科技奖一等奖（排名第一），曾获得科技部创新创业人才、南京市领军人才、科技创业家等称号。
[1]鄢永胜. 蛋白多肽类药物的药代动力学[J]. 咸宁学院学报, 2004, 24(3):100-104.
[2]Yun Y, Cho Y W, Park K. Nanoparticles for oral delivery:targeted nanoparticles with peptidic ligands for oral protein delivery[J]. Adv Drug Deliver Rev, 2013, 65(6):822-832.Yun Y, Cho Y W, Park K. Nanoparticles for oral delivery:targeted nanoparticles with peptidic ligands for oral protein delivery[J]. Adv Drug Deliver Rev, 2013, 65(6):822-832.
[3]Antunes F, Andrade F, Ferreira D, et al. Models to predict intestinal absorption of therapeutic peptides and proteins[J]. Curr Drug Metab, 2013, 14(1):4-20.Antunes F, Andrade F, Ferreira D, et al. Models to predict intestinal absorption of therapeutic peptides and proteins[J]. Curr Drug Metab, 2013, 14(1):4-20.
[4]Kagan L. Pharmacokinetic modeling of the subcutaneous absorption of therapeutic proteins[J]. Drug Metab Dispos, 2014, 42(11):1890-1905.Kagan L. Pharmacokinetic modeling of the subcutaneous absorption of therapeutic proteins[J]. Drug Metab Dispos, 2014, 42(11):1890-1905.
[5]Diao L, Meibohm B. Pharmacokinetics and pharmacokineticpharmacodynamic correlations of therapeutic peptides[J]. Clin Pharmacokinet, 2013, 52(10):855-868.Diao L, Meibohm B. Pharmacokinetics and pharmacokineticpharmacodynamic correlations of therapeutic peptides[J]. Clin Pharmacokinet, 2013, 52(10):855-868.
[6]Han C, Li Y, Sun M, et al. Small peptide-modified nanostructured lipid carriers distribution and targeting to EGFR-overexpressing tumor in vivo[J]. Artif Cells Nanomed Biotechnol, 2014, 42(3):161-166.Han C, Li Y, Sun M, et al. Small peptide-modified nanostructured lipid carriers distribution and targeting to EGFR-overexpressing tumor in vivo[J]. Artif Cells Nanomed Biotechnol, 2014, 42(3):161-166.
[7]Yuan Z X, He X K, Wu X J, et al. Peptide fragments of human serum albumin as novel renal targeting carriers[J]. Int J Pharm, 2014,460(1/2):196-204.Yuan Z X, He X K, Wu X J, et al. Peptide fragments of human serum albumin as novel renal targeting carriers[J]. Int J Pharm, 2014,460(1/2):196-204.
[8]Ding J, Feng M, Wang F, et al. Targeting effect of PEGylated liposomes modified with the Arg-Gly-Asp sequence on gastric cancer[J]. Oncol Rep, 2015, 34(4):1825-1834.Ding J, Feng M, Wang F, et al. Targeting effect of PEGylated liposomes modified with the Arg-Gly-Asp sequence on gastric cancer[J]. Oncol Rep, 2015, 34(4):1825-1834.
[9]Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics[J]. J Clin Pharmacol, 2012, 52(S1):54S-62S.Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics[J]. J Clin Pharmacol, 2012, 52(S1):54S-62S.
[10]Shi S, Liu Y, Li Z, et al. Pharmacokinetics, pharmacodynamics, and tolerability of a generic formulation of exenatide:a randomized, openlabel, single-and multiple-dose study in healthy Chinese volunteers[J]. Arzneim Forsch, 2012, 62(2):75-82.Shi S, Liu Y, Li Z, et al. Pharmacokinetics, pharmacodynamics, and tolerability of a generic formulation of exenatide:a randomized, openlabel, single-and multiple-dose study in healthy Chinese volunteers[J]. Arzneim Forsch, 2012, 62(2):75-82.
[11]LoRusso P M, Venkatakrishnan K, Ramanathan R K, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction:phase I NCI Organ Dysfunction Working Group Study NCI-6432[J]. Clin Cancer Res, 2012, 18(10):2954-2963.LoRusso P M, Venkatakrishnan K, Ramanathan R K, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction:phase I NCI Organ Dysfunction Working Group Study NCI-6432[J]. Clin Cancer Res, 2012, 18(10):2954-2963.
[12]Vickers A E, Fischer V, Connors S, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices. Comparison to rat and dog slices and human cell lines[J]. Drug Metab Dispos, 1992, 20(6):802-809.Vickers A E, Fischer V, Connors S, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices. Comparison to rat and dog slices and human cell lines[J]. Drug Metab Dispos, 1992, 20(6):802-809.
[13]Wang Y M, Krzyzanski W, Doshi S, et al. Pharmacodynamics mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects[J]. AAPS J, 2010, 12(4):729-740.Wang Y M, Krzyzanski W, Doshi S, et al. Pharmacodynamics mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects[J]. AAPS J, 2010, 12(4):729-740.
[14]Di L. Strategic approaches to optimizing peptide ADME properties[J]. AAPS J, 2015, 17(1):134-143.Di L. Strategic approaches to optimizing peptide ADME properties[J]. AAPS J, 2015, 17(1):134-143.
[15]Welch B D, Francis J N, Redman J S, et al. Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance[J]. J Virol, 2010, 84(21):11235-11244.Welch B D, Francis J N, Redman J S, et al. Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance[J]. J Virol, 2010, 84(21):11235-11244.
[16]Lee K H, Catherine C, Kim D M. Enhanced production of unnatural amino acid-containing proteins in a cell-free protein synthesis system[J]. J Ind Eng Chem, 2016, 37:90-94.Lee K H, Catherine C, Kim D M. Enhanced production of unnatural amino acid-containing proteins in a cell-free protein synthesis system[J]. J Ind Eng Chem, 2016, 37:90-94.
[17]Schultz Y P G. Production of carrier-peptide conjugates using chemically reactive unnatural amino acids:US, 9109022[P]. 2015-08-18.Schultz Y P G. Production of carrier-peptide conjugates using chemically reactive unnatural amino acids:US, 9109022[P]. 2015-08-18.
[18]Knoop A, Thomas A, Fichant E, et al. Qualitative identification of growth hormone-releasing hormones in human plasma by means of immunoaffinity purification and LC-HRMS/MS[J]. Anal Bioanal Chem, 2016, 408(12):3145-3153.Knoop A, Thomas A, Fichant E, et al. Qualitative identification of growth hormone-releasing hormones in human plasma by means of immunoaffinity purification and LC-HRMS/MS[J]. Anal Bioanal Chem, 2016, 408(12):3145-3153.
[19]Chee S M Q, Wongsantichon J, Siau J, et al. Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids[J]. PLoS One, 2017, 12(12):e0189379. Doi:10.1371/journal.pone.0189379.Chee S M Q, Wongsantichon J, Siau J, et al. Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids[J]. PLoS One, 2017, 12(12):e0189379. Doi:10.1371/journal.pone.0189379.
[20]Debruyne F, Tzvetkov M, Altarac S, et al. Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia[J]. Urology, 2010, 76(4):927-933.Debruyne F, Tzvetkov M, Altarac S, et al. Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia[J]. Urology, 2010, 76(4):927-933.
[21]Heredi-Szabo K, Murphy R, Lovas S. Is IGnRH-Ⅲ the most potent GnRH analog containing only natural amino acids that specifically inhibits the growth of human breast cancer cells?[J]. J Pept Sci, 2010, 12(11):714-720.Heredi-Szabo K, Murphy R, Lovas S. Is IGnRH-Ⅲ the most potent GnRH analog containing only natural amino acids that specifically inhibits the growth of human breast cancer cells?[J]. J Pept Sci, 2010, 12(11):714-720.
[22]Scholtz H E, Pretorius S G, Wessels D H, et al. Pharmacokinetic and glucodynamic variability:assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique[J]. Diabetologia, 2005, 48(10):1988-1995.Scholtz H E, Pretorius S G, Wessels D H, et al. Pharmacokinetic and glucodynamic variability:assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique[J]. Diabetologia, 2005, 48(10):1988-1995.
[23]Nnane I P, Han C, Jiao Q, et al. Modification of the Fc region of a human anti-oncostatin M monoclonal antibody for higher affinity to FcRn and extension of half-life in cynomolgus monkeys[J]. Basic Clin Pharmacol, 2017, 121(1):13-21.Nnane I P, Han C, Jiao Q, et al. Modification of the Fc region of a human anti-oncostatin M monoclonal antibody for higher affinity to FcRn and extension of half-life in cynomolgus monkeys[J]. Basic Clin Pharmacol, 2017, 121(1):13-21.
[24]Sockolosky J T, Kivimäe S, Szoka F C. Fusion of a short peptide that binds immunoglobulin G to a recombinant protein substantially increases its plasma half-life in mice[J]. PLoS One, 2014, 9(7):e102566. Doi:10.1371/journal.pone.0102566.Sockolosky J T, Kivimäe S, Szoka F C. Fusion of a short peptide that binds immunoglobulin G to a recombinant protein substantially increases its plasma half-life in mice[J]. PLoS One, 2014, 9(7):e102566. Doi:10.1371/journal.pone.0102566.
[25]Hao J, Guo Y, Song X, et al. Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris[J]. Microb Cell Fact, 2016, 15(1):209. Doi:10.1186/s12934-016-0601-9.Hao J, Guo Y, Song X, et al. Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris[J]. Microb Cell Fact, 2016, 15(1):209. Doi:10.1186/s12934-016-0601-9.
[26]Strohl W R. Fusion proteins for half-life extension of biologics as a strategy to make biobetters[J]. BioDrugs, 2015, 29(4):215-239.Strohl W R. Fusion proteins for half-life extension of biologics as a strategy to make biobetters[J]. BioDrugs, 2015, 29(4):215-239.
[27]Kim D, Jeon H, Ahn S, et al. An approach for half-life extension and activity preservation of an anti-diabetic peptide drug based on genetic fusion with an albumin-binding aptide[J]. J Controlled Release, 2017, 256:114-120.Kim D, Jeon H, Ahn S, et al. An approach for half-life extension and activity preservation of an anti-diabetic peptide drug based on genetic fusion with an albumin-binding aptide[J]. J Controlled Release, 2017, 256:114-120.
[28]Tan Z P, Wang L X. Chemical Biology of Glycoproteins[M]. Cambridge:Thomas Graham House, 2017:394-414.Tan Z P, Wang L X. Chemical Biology of Glycoproteins[M]. Cambridge:Thomas Graham House, 2017:394-414.
[29]Chung H S, Kim J S, Sang M L, et al. Additional N-glycosylation in the N-terminal region of recombinant human alpha-1 antitrypsin enhances the circulatory half-life in Sprague-Dawley rats[J]. Glycoconjugate J, 2016, 33(2):1-8.Chung H S, Kim J S, Sang M L, et al. Additional N-glycosylation in the N-terminal region of recombinant human alpha-1 antitrypsin enhances the circulatory half-life in Sprague-Dawley rats[J]. Glycoconjugate J, 2016, 33(2):1-8.
[30]Rao L, Ma Y, Zhuang M J, et al. Chitosan-decorated selenium nanoparticles as protein carriers to improve the in vivo half-life of the peptide therapeutic BAY 55-9837 for type 2 diabetes mellitus[J]. Int J Nanomed, 2014, 9(1):4819-4828.Rao L, Ma Y, Zhuang M J, et al. Chitosan-decorated selenium nanoparticles as protein carriers to improve the in vivo half-life of the peptide therapeutic BAY 55-9837 for type 2 diabetes mellitus[J]. Int J Nanomed, 2014, 9(1):4819-4828.
[31]Rubin S J S, Tal-Gan Y, Gilon C, et al. Conversion of protein active regions into peptidomimetic therapeutic leads using backbone cyclization and cycloscan-how to do it yourself[J]. Curr Top Med Chem, 2018, 18(7):556-565.Rubin S J S, Tal-Gan Y, Gilon C, et al. Conversion of protein active regions into peptidomimetic therapeutic leads using backbone cyclization and cycloscan-how to do it yourself[J]. Curr Top Med Chem, 2018, 18(7):556-565.
[32]Räder A F B, Reichart F, Weinmüller M, et al. Improving oral bioavailability of cyclic peptides by N-methylation.[J]. Bioorgan Med Chem, 2018, 26(10):2766-2773.Räder A F B, Reichart F, Weinmüller M, et al. Improving oral bioavailability of cyclic peptides by N-methylation.[J]. Bioorgan Med Chem, 2018, 26(10):2766-2773.
[33]Harris A G. Somatostatin and somatostatin analogues:pharmacokinetics and pharmacodynamic effects[J]. Gut, 1994, 35:S1-S4.Harris A G. Somatostatin and somatostatin analogues:pharmacokinetics and pharmacodynamic effects[J]. Gut, 1994, 35:S1-S4.
[34]Al-Salama Z T, Syed Y Y. Plecanatide:first global approval[J]. Drugs, 2017, 77(5):593-598.Al-Salama Z T, Syed Y Y. Plecanatide:first global approval[J]. Drugs, 2017, 77(5):593-598.
[35]Böhme D, Becksickinger A G. Controlling toxicity of Peptide-drug conjugates by different chemical linker structures[J]. ChemMedChem, 2015, 55(5):804-814.Böhme D, Becksickinger A G. Controlling toxicity of Peptide-drug conjugates by different chemical linker structures[J]. ChemMedChem, 2015, 55(5):804-814.
[36]Deyle K, Kong X D, Heinis C. Phage selection of cyclic peptides for application in research and drug development[J]. Acc Chem Res, 2017, 50(8):1866-1874.Deyle K, Kong X D, Heinis C. Phage selection of cyclic peptides for application in research and drug development[J]. Acc Chem Res, 2017, 50(8):1866-1874.
[37]Van Witteloostuijn S B, Pedersen S L, Jensen K J. Half-life extension of biopharmaceuticals using chemical methods:alternatives to PEGylation[J]. ChemMedChem, 2016, 11(22):2474-2495.Van Witteloostuijn S B, Pedersen S L, Jensen K J. Half-life extension of biopharmaceuticals using chemical methods:alternatives to PEGylation[J]. ChemMedChem, 2016, 11(22):2474-2495.
[38]Stidl R, Fuchs S, Bossard M, et al. Safety of PEGylated recombinant human full-length coagulation factor VⅢ (BAX 855) in the overall context of PEG and PEG conjugates[J]. Haemophilia, 2016, 22(1):54-64.Stidl R, Fuchs S, Bossard M, et al. Safety of PEGylated recombinant human full-length coagulation factor VⅢ (BAX 855) in the overall context of PEG and PEG conjugates[J]. Haemophilia, 2016, 22(1):54-64.
[39]Mcvicar S D, Rayavara K, Carney D H. Radiomitigation and tissue repair activity of systemically administered therapeutic peptide TP508 is enhanced by PEGylation[J]. AAPS J, 2017, 19(3):743-753.Mcvicar S D, Rayavara K, Carney D H. Radiomitigation and tissue repair activity of systemically administered therapeutic peptide TP508 is enhanced by PEGylation[J]. AAPS J, 2017, 19(3):743-753.
[40]Ding S, Song M, Sim B C, et al. Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility[J]. Bioconjugate Chem, 2014, 25(7):1351-1359.Ding S, Song M, Sim B C, et al. Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility[J]. Bioconjugate Chem, 2014, 25(7):1351-1359.
[41]Gebauer M, Skerra A. Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action[J]. Bioorgan Med Chem, 2017, 26(10):2882-2887.Gebauer M, Skerra A. Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action[J]. Bioorgan Med Chem, 2017, 26(10):2882-2887.
[42]Liebner R, Mathaes R, Meyer M, et al. Protein HESylation for halflife extension:synthesis, characterization and pharmacokinetics of HESylated anakinra[J]. Eur J Pharm Biopharm, 2014, 87(2):378-385.Liebner R, Mathaes R, Meyer M, et al. Protein HESylation for halflife extension:synthesis, characterization and pharmacokinetics of HESylated anakinra[J]. Eur J Pharm Biopharm, 2014, 87(2):378-385.
[43]LaBelle J L, Katz S G, Bird G H, et al. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers[J]. J Clin Investig, 2012, 122(6):2018-2031.LaBelle J L, Katz S G, Bird G H, et al. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers[J]. J Clin Investig, 2012, 122(6):2018-2031.
[44]The Endocrine Society. SAT 109-133-GHRH, GH & IGF biology & signaling:long-acting GHRH analog ALRN-5281, the first stapled peptide clinical candidate, exhibits robust in vitro and in vivo activation of the growth hormone pathway[R]. Cambridge:Aileron Therapeutics, 2013.The Endocrine Society. SAT 109-133-GHRH, GH & IGF biology & signaling:long-acting GHRH analog ALRN-5281, the first stapled peptide clinical candidate, exhibits robust in vitro and in vivo activation of the growth hormone pathway[R]. Cambridge:Aileron Therapeutics, 2013.
[45]Rezaei Araghi R, Ryan J A, Letai A, et al. Rapid optimization of Mcl-1 inhibitors using stapled peptide libraries including non-natural side chains[J]. ACS Chem Biol, 2016, 11(5):1238-1244.Rezaei Araghi R, Ryan J A, Letai A, et al. Rapid optimization of Mcl-1 inhibitors using stapled peptide libraries including non-natural side chains[J]. ACS Chem Biol, 2016, 11(5):1238-1244.
[46]Payton M, Pinchasik D, Mehta A, et al. 1039TiP Phase 2a study of a novel stapled peptide ALRN-6924 disrupting MDMX-and MDM2-mediated inhibition of wild-type TP53 in patients with peripheral T-cell lymphoma[J]. Ann Oncol, 2017, 28(5). Doi:10.1093/annonc/mdx373.045.Payton M, Pinchasik D, Mehta A, et al. 1039TiP Phase 2a study of a novel stapled peptide ALRN-6924 disrupting MDMX-and MDM2-mediated inhibition of wild-type TP53 in patients with peripheral T-cell lymphoma[J]. Ann Oncol, 2017, 28(5). Doi:10.1093/annonc/mdx373.045.
[47]Cromm P M, Spiegel J, Grossmann T N. Hydrocarbon stapled peptides as modulators of biological function[J]. ACS Chem Biol, 2015, 10(6):1362-1375.Cromm P M, Spiegel J, Grossmann T N. Hydrocarbon stapled peptides as modulators of biological function[J]. ACS Chem Biol, 2015, 10(6):1362-1375.
[48]Liu D, Yang F, Xiong F, et al. The smart drug delivery system and its clinical potential[J]. Theranostics, 2016, 6(9):1306-1323.Liu D, Yang F, Xiong F, et al. The smart drug delivery system and its clinical potential[J]. Theranostics, 2016, 6(9):1306-1323.
[49]Teekamp N, Van Dijk F, Broesder A, et al. Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney[J]. Int J Pharm, 2017, 534(1):229-236.Teekamp N, Van Dijk F, Broesder A, et al. Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney[J]. Int J Pharm, 2017, 534(1):229-236.
刘梦,于彭城,徐寒梅.蛋白多肽类药物长效化技术研究进展[J].药学进展,2019,43(03):209-216.
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