功能肽合成和挖掘策略研究进展

doi:10.12211/2096-8280.2024-067

合成生物学 ›› 2025, Vol. 6 ›› Issue (2): 461-478.DOI: 10.12211/2096-8280.2024-067

功能肽合成和挖掘策略研究进展

汤传根¹^,²^,³^,⁴, 王璟¹, 张烁¹, 张昊宁¹, 康振²^,⁴

^1.南京汉欣医药科技有限公司，江苏南京 210033
^2.江南大学，未来食品科学中心，江苏无锡 214122
^3.江南大学生物工程学院，工业生物技术教育部重点实验室，江苏无锡 214122
^4.江南大学生物工程学院，糖化学与生物技术教育部重点实验室，江苏无锡 214122

收稿日期:2024-08-28 修回日期:2024-11-11 出版日期:2025-04-30 发布日期:2025-05-20
通讯作者: 汤传根
作者简介:汤传根（1985—），男，博士研究生，工程师。研究方向为重组多肽/蛋白药物、合成多肽药物、功能肽研究、合成生物学产业化应用。E-mail：rootyt@hanxinpharm.com

Advances in synthesis and mining strategies for functional peptides

TANG Chuan′gen¹^,²^,³^,⁴, WANG Jing¹, ZHANG Shuo¹, ZHANG Haoning¹, KANG Zhen²^,⁴

^1.Nanjing Hanxin Pharmaceutical Technology Co. ，Ltd. ，Nanjing 210033，Jiangsu，China
^2.Science Center for Future Foods，Jiangnan University，Wuxi 214122，Jiangsu，China
^3.Key Laboratory of Industrial Biotechnology，Ministry of Education，School of Biotechnology，Jiangnan University，Wuxi 214122，Jiangsu，China
^4.Key Laboratory of Carbohydrate Chemistry and Biotechnology，Ministry of Education，School of Biotechnology，Jiangnan University，Wuxi 214122，Jiangsu，China

Received:2024-08-28 Revised:2024-11-11 Online:2025-04-30 Published:2025-05-20
Contact: TANG Chuan′gen

摘要/Abstract

摘要：

功能肽是由2～50个氨基酸组成的短链肽，近年来因其特异性强、作用迅速及副作用低而成为开发新药和功能原料的重要研究热点。首先，本文梳理了功能肽的分类、作用机制及应用场景，总结了不同类型功能肽的特点和在生物医药、食品科学及化妆品等领域的应用。接着，针对功能肽的合成方法，探讨了化学合成与生物合成的最新进展，比较了这两种制备工艺的优缺点以及各自的适用场景。在功能肽挖掘策略方面，本文综述了噬菌体表面展示技术、机器学习算法、分子对接技术及人工智能技术等方面的最新研究，这些技术在功能肽的筛选和设计中展现出重要潜力，提升了研究的效率与准确性。展望未来，功能肽的研究将面临新的挑战与机遇。如何改进合成工艺以提高效率，如何通过结构修饰提高功能肽稳定性，以及如何利用计算机辅助优化和人工智能设计多功能肽，将成为重要的研究方向。同时，加强功能肽的安全性和有效性的评估能进一步提升功能肽的应用潜力。

关键词: 功能肽, 合成生物学, 生物合成, 高通量, 机器学习

Abstract:

Functional peptides are short chain peptides composed of 2 to 50 amino acids, and their biological activities are closely related to their amino acid sequences, chain length, and structural architectures. Functional peptides can play a regulatory role in a variety of physiological processes by specifically recognizing and binding to target molecules in vivo. Due to their rapid action, strong specificity, less side effect and toxicity, functional peptides have shown great application potentials in many fields such as biomedicine, food science and cosmetics. For example, in the field of biomedicine, functional peptides can be used as the basic material of antimicrobe, anticancer, immune regulation and other therapeutic factors. In the food industry, they are used as natural supplements to enhance nutritional value for health benefit. In the field of cosmetics, functional peptides are widely used for the anti-aging, moisturizing, and repairing of the skin. In this paper, we discuss the ways of obtaining functional peptides, mainly including protein hydrolysis, chemical synthesis, and biosynthesis (e.g., through microbial recombinant expression technology), and compare their advantages and disadvantages and respective application scenarios. In terms of strategies for mining functional peptides, we review the latest research progress including phage surface display, machine learning algorithm, molecular docking and artificial intelligence. These techniques show significant potentials in the screening and design of functional peptides. In recent years, the rapid development of synthetic biology and the wide applications of bioinformatics and artificial intelligence have provided new ideas and strategies for the discovery and optimization of functional peptides, making it possible to screen functional peptides through machine learning and high throughput. Looking forward to the future, the research of functional peptides will face new challenges and opportunities. Improving the synthesis process for high efficiency, improving the stability of functional peptides through structural modifications, and using computer-aided optimization and artificial intelligence to design multifunctional peptides will become important research directions. At the same time, strengthening the safety and efficacy assessment of functional peptides can further enhance the applications of functional peptides.

Key words: functional peptide, synthetic biology, biosynthesis, high throughput, machine learning

中图分类号:

Q815

汤传根, 王璟, 张烁, 张昊宁, 康振. 功能肽合成和挖掘策略研究进展[J]. 合成生物学, 2025, 6(2): 461-478.

TANG Chuan′gen, WANG Jing, ZHANG Shuo, ZHANG Haoning, KANG Zhen. Advances in synthesis and mining strategies for functional peptides[J]. Synthetic Biology Journal, 2025, 6(2): 461-478.

图/表 6

参考文献 67

68	陈清, 曾鑫, 彭永亮, 等. 重组串联融合蛋白制备目标多肽的方法: ZL201910563692.3[P]. 2022-05-13.
	CHEN Q, ZENG X, PENG Y L,et al. Method for preparing target polypeptide by recombinant tandem fusion protein ZL201910563692.3[P]. 2022-05-13.
69	ZHANG L C, WEI D D, ZHAN N, et al. Heterologous expression of the novel α-helical hybrid peptide PR-FO in Bacillus subtilis [J]. Bioprocess and Biosystems Engineering, 2020, 43(9): 1619-1627.
70	CHEN M L, LIN N F, LIU X D, et al. A novel antimicrobial peptide screened by a Bacillus subtilis expression system, derived from Larimichthys crocea Ferritin H, exerting bactericidal and parasiticidal activities[J]. Frontiers in Immunology, 2023, 14: 1168517.
71	SUN W F, WU Y M, DING W W, et al. An auto-inducible expression and high cell density fermentation of Beefy Meaty Peptide with Bacillus subtilis [J]. Bioprocess and Biosystems Engineering, 2020, 43(4): 701-710.
72	FU G, YUE J, LI D D, et al. An operator-based expression toolkit for Bacillus subtilis enables fine-tuning of gene expression and biosynthetic pathway regulation[J]. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(11): e2119980119.
73	LU Z H, YANG S H, YUAN X, et al. CRISPR-assisted multi-dimensional regulation for fine-tuning gene expression in Bacillus subtilis [J]. Nucleic Acids Research, 2019, 47(7): e40.
74	ZHU X Y, LUO H, YU X R, et al. Genome-wide CRISPRi screening of key genes for recombinant protein expression in Bacillus subtilis [J]. Advanced Science, 2024, 11(33): 2404313.
75	ILGEN C, LIN‐CEREGHINO J, CREGG J M. Pichia pastoris[M/OL]//GELLISSEN G. Production of recombinant proteins. 1st ed. New York: Wiley, 2004: 143-162 [2024-08-08]. .
76	KARBALAEI M, REZAEE S A, FARSIANI H. Pichia pastoris: a highly successful expression system for optimal synthesis of heterologous proteins[J]. Journal of Cellular Physiology, 2020, 235(9): 5867-5881.
77	CAO X T, ZHANG Y, MAO R Y, et al. Design and recombination expression of a novel plectasin-derived peptide MP1106 and its properties against Staphylococcus aureus [J]. Applied Microbiology and Biotechnology, 2015, 99(6): 2649-2662.
78	ZHANG K, YANG N, TENG D, et al. Expression and characterization of the new antimicrobial peptide AP138L-arg26 anti Staphylococcus aureus [J]. Applied Microbiology and Biotechnology, 2024, 108(1): 111.
79	CAO J C, DE LA FUENTE-NUNEZ C, OU R W, et al. Yeast-based synthetic biology platform for antimicrobial peptide production[J]. ACS Synthetic Biology, 2018, 7(3): 896-902.
80	LI X H, FAN Y, LIN Q, et al. Expression of chromogranin A-derived antifungal peptide CGA-N12 in Pichia pastoris [J]. Bioengineered, 2020, 11(1): 318-327.
81	RENYE J A JR, SOMKUTI G A. Nisin-induced expression of a recombinant antihypertensive peptide in dairy lactic acid bacteria[J]. Biotechnology Letters, 2015, 37(7): 1447-1454.
82	HUYNH E, LI J L. Generation of Lactococcus lactis capable of coexpressing epidermal growth factor and trefoil factor to enhance in vitro wound healing[J]. Applied Microbiology and Biotechnology, 2015, 99(11): 4667-4677.
83	NONGONIERMA A B, O’KEEFFE M B, FITZGERALD R J. Milk protein hydrolysates and bioactive peptides[M/OL]//MCSWEENEY P L H, O’MAHONY J A. Advanced dairy chemistry: volume 1B: proteins: applied aspects. New York, NY: Springer New York, 2016: 417-482 [2024-08-10]. .
84	LIAO W, JAHANDIDEH F, FAN H B, et al. Egg protein-derived bioactive peptides: preparation, efficacy, and absorption[M/OL]//Advances in food and nutrition research. New York: Elsevier, 2018, 85: 1-58 [2024-08-10]. .
85	SMITH G P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface[J]. Science, 1985, 228(4705): 1315-1317.
86	FLING M, HOROWITZ N H, HEINEMANN S F. The isolation and properties of crystalline tyrosinase from Neurospora [J]. Journal of Biological Chemistry, 1963, 238(6): 2045-2053.
87	SUN Y J, SHUKLA G S, WEAVER D, et al. Phage-display selection on tumor histological specimens with laser capture microdissection[J]. Journal of Immunological Methods, 2009, 347(1-2): 46-53.
88	YANG M, LIU C W, NIU M C, et al. Phage-display library biopanning and bioinformatic analysis yielded a high-affinity peptide to inflamed vascular endothelium both in vitro and in vivo [J]. Journal of Controlled Release, 2014, 174: 72-80.
89	GUAN M Q, WANG J, YANG L B, et al. Targeting osteosarcoma vasculature with peptide obtained by phage display[J]. Contemporary Oncology/ Współczesna Onkologia, 2014, 18(3): 165-170.
90	ZHOU C, KANG J L, WANG X X, et al. Phage display screening identifies a novel peptide to suppress ovarian cancer cells in vitro and in vivo in mouse models[J]. BMC Cancer, 2015, 15: 889.
91	WENG X J, LIAO Q D, LI K H, et al. Screening serum biomarker of knee osteoarthritis using a phage display technique[J]. Clinical Biochemistry, 2012, 45(4-5): 303-308.
92	YIN L, LUO Y Z, LIANG B, et al. Specific ligands for classical swine fever virus screened from landscape phage display library[J]. Antiviral Research, 2014, 109: 68-71.
93	LIU Z P, LIU J F, WANG K, et al. Selection of phage-displayed peptides for the detection of imidacloprid in water and soil[J]. Analytical Biochemistry, 2015, 485: 28-33.
94	CHEN Y P, SHEN Y Y, GUO X, et al. Transdermal protein delivery by a coadministered peptide identified via phage display[J]. Nature Biotechnology, 2006, 24(4): 455-460.
95	DUERR D M, WHITE S J, SCHLUESENER H J. Identification of peptide sequences that induce the transport of phage across the gastrointestinal mucosal barrier[J]. Journal of Virological Methods, 2004, 116(2): 177-180.
96	PASQUALINI R, RUOSLAHTI E. Organ targeting in vivo using phage display peptide libraries[J]. Nature, 1996, 380(6572): 364-366.
97	ZHANG X C, ZHANG X Y, GAO H L, et al. Phage display derived peptides for Alzheimer’s disease therapy and diagnosis[J]. Theranostics, 2022, 12(5): 2041-2062.
98	MANAVALAN B, BASITH S, SHIN T H, et al. MLACP: machine-learning-based prediction of anticancer peptides[J]. Oncotarget, 2017, 8(44): 77121-77136.
99	GUPTA S, SHARMA A K, SHASTRI V, et al. Prediction of anti-inflammatory proteins/peptides: an in silico approach[J]. Journal of Translational Medicine, 2017, 15(1): 7.
100	ILYAS S, LEE J, HWANG Y, et al. Deciphering Cathepsin K inhibitors: a combined QSAR, docking and MD simulation based machine learning approaches for drug design[J]. SAR and QSAR in Environmental Research, 2024, 35(9): 771-793.
101	GULL S, SHAMIM N, MINHAS F. AMAP: hierarchical multi-label prediction of biologically active and antimicrobial peptides[J]. Computers in Biology and Medicine, 2019, 107: 172-181.
102	CHO C Y, LEE S S, BANG D M, et al. ChemAP: predicting drug approval with chemical structures before clinical trial phase by leveraging multi-modal embedding space and knowledge distillation[J]. Scientific Reports, 2024, 14(1): 23010.
1	HARTMANN R, MEISEL H. Food-derived peptides with biological activity: from research to food applications[J]. Current Opinion in Biotechnology, 2007, 18(2): 163-169.
2	KITTS D D, WEILER K. Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery[J]. Current Pharmaceutical Design, 2003, 9(16): 1309-1323.
3	HANCOCK R E W, SAHL H G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies[J]. Nature Biotechnology, 2006, 24(12): 1551-1557.
4	WANG G S, LI X, WANG Z. APD3: the antimicrobial peptide database as a tool for research and education[J]. Nucleic Acids Research, 2016, 44(D1): D1087-D1093.
5	MENDIS E, RAJAPAKSE N, BYUN H G, et al. Investigation of jumbo squid (Dosidicus gigas) skin gelatin peptides for their in vitro antioxidant effects[J]. Life Sciences, 2005, 77(17): 2166-2178.
6	SUETSUNA K. Antioxidant peptides from the protease digest of prawn (Penaeus japonicus) muscle[J]. Marine Biotechnology, 2000, 2(1): 5-10.
7	SARMADI B H, ISMAIL A. Antioxidative peptides from food proteins: a review[J]. Peptides, 2010, 31(10): 1949-1956.
8	PIHLANTO A. Antioxidative peptides derived from milk proteins[J]. International Dairy Journal, 2006, 16(11): 1306-1314.
9	FREITAS A C, ANDRADE J C, SILVA F M, et al. Antioxidative peptides: trends and perspectives for future research[J]. Current Medicinal Chemistry, 2013, 20(36): 4575-4594.
10	ZHANG X L, ZHUANG H, WU S J, et al. Marine bioactive peptides: anti-photoaging mechanisms and potential skin protective effects[J]. Current Issues in Molecular Biology, 2024, 46(2): 990-1009.
11	DOUNGAPAI C, SIRIWOHARN T, MALILA Y, et al. UV-B protective and antioxidant activities of protein hydrolysate from sea cucumber (Holothuria scabra) using enzymatic hydrolysis[J]. Frontiers in Marine Science, 2022, 9: 892255.
12	ZHANG Y H, WANG C, ZHANG W H, et al. Bioactive peptides for anticancer therapies[J]. Biomaterials Translational, 2023, 4(1): 5-17.
13	WANG L H, DONG C, LI X, et al. Anticancer potential of bioactive peptides from animal sources (Review)[J]. Oncology Reports, 2017, 38(2): 637-651.
103	GIGUÈRE S, LAVIOLETTE F, MARCHAND M, et al. Machine learning assisted design of highly active peptides for drug discovery[J]. PLoS Computational Biology, 2015, 11(4): e1004074.
104	JOO S H, PEI D H. Synthesis and screening of support-bound combinatorial peptide libraries with free C-termini: determination of the sequence specificity of PDZ domains[J]. Biochemistry, 2008, 47(9): 3061-3072.
105	FANG C, MORIWAKI Y, LI C H, et al. Prediction of antifungal peptides by deep learning with character embedding[J]. IPSJ Transactions on Bioinformatics, 2019, 12: 21-29.
106	AGRAWAL P, BHALLA S, CHAUDHARY K, et al. In silico approach for prediction of antifungal peptides[J]. Frontiers in Microbiology, 2018, 9: 323.
107	BJERRUM E J, SATTAROV B. Improving chemical autoencoder latent space and molecular de novo generation diversity with heteroencoders[J]. Biomolecules, 2018, 8(4): 131.
108	CAO D S, LIU S, XU Q S, et al. Large-scale prediction of drug-target interactions using protein sequences and drug topological structures[J]. Analytica Chimica Acta, 2012, 752: 1-10.
109	KAO P Y, YANG Y C, CHIANG W Y, et al. Exploring the advantages of quantum generative adversarial networks in generative chemistry[J]. Journal of Chemical Information and Modeling, 2023, 63(11): 3307-3318.
110	MÜLLER A T, HISS J A, SCHNEIDER G. Recurrent neural network model for constructive peptide design[J]. Journal of Chemical Information and Modeling, 2018, 58(2): 472-479.
111	MA Y, GUO Z Y, XIA B B, et al. Identification of antimicrobial peptides from the human gut microbiome using deep learning[J]. Nature Biotechnology, 2022, 40(6): 921-931.
112	KHABBAZ H, KARIMI-JAFARI M H, SABOURY A A, et al. Prediction of antimicrobial peptides toxicity based on their physico-chemical properties using machine learning techniques[J]. BMC Bioinformatics, 2021, 22(1): 549.
113	XIAO X, WANG P, LIN W Z, et al. iAMP-2L: a two-level multi-label classifier for identifying antimicrobial peptides and their functional types[J]. Analytical Biochemistry, 2013, 436(2): 168-177.
114	WEI L Y, ZHOU C, CHEN H R, et al. ACPred-FL: a sequence-based predictor using effective feature representation to improve the prediction of anti-cancer peptides[J]. Bioinformatics, 2018, 34(23): 4007-4016.
14	SOON T N, CHIA A Y Y, YAP W H, et al. Anticancer mechanisms of bioactive peptides[J]. Protein & Peptide Letters, 2020, 27(9): 823-830.
15	PAVLICEVIC M, MARMIROLI N, MAESTRI E. Immunomodulatory peptides: a promising source for novel functional food production and drug discovery[J]. Peptides, 2022, 148: 170696.
16	CLEMENTE A. Enzymatic protein hydrolysates in human nutrition[J]. Trends in Food Science & Technology, 2000, 11(7): 254-262.
17	KORHONEN H, PIHLANTO A. Bioactive peptides: production and functionality[J]. International Dairy Journal, 2006, 16(9): 945-960.
18	UDENIGWE C C, ALUKO R E. Food protein-derived bioactive peptides: production, processing, and potential health benefits[J]. Journal of Food Science, 2012, 77(1): R11-R24.
19	ALTMANN S E, JONES J C, SCHULTZ-CHERRY S, et al. Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide[J]. Virology, 2009, 388(2): 248-259.
20	WANG Y G, WANG X, ZHANG Y F, et al. RGD-modified polymeric micelles as potential carriers for targeted delivery to integrin-overexpressing tumor vasculature and tumor cells[J]. Journal of Drug Targeting, 2009, 17(6): 459-467.
21	NGOC L T N, MOON J Y, LEE Y C. Insights into bioactive peptides in cosmetics[J]. Cosmetics, 2023, 10(4): 111.
22	ZHAO W, YANG A Q, WANG J, et al. Potential application of natural bioactive compounds as skin-whitening agents: a review[J]. Journal of Cosmetic Dermatology, 2022, 21(12): 6669-6687.
23	SURYANINGTYAS I T, JE J Y. Bioactive peptides from food proteins as potential anti-obesity agents: mechanisms of action and future perspectives[J]. Trends in Food Science & Technology, 2023, 138: 141-152.
24	KUMAR M S. Peptides and peptidomimetics as potential antiobesity agents: overview of current status[J]. Frontiers in Nutrition, 2019, 6: 11.
25	MUTTENTHALER M, KING G F, ADAMS D J, et al. Trends in peptide drug discovery[J]. Nature Reviews Drug Discovery, 2021, 20(4): 309-325.
115	丁明珠, 李炳志, 王颖, 等. 合成生物学重要研究方向进展[J]. 合成生物学, 2020, 1(1): 7-28.
	DING M Z, LI B Z, WANG Y, et al. Significant research progress in synthetic biology[J]. Synthetic Biology Journal, 2020, 1(1): 7-28.
116	KOWALCZYK R, HARRIS P W R, WILLIAMS G M, et al. Peptide lipidation-a synthetic strategy to afford peptide based therapeutics[M/OL]. Advances in experimental medicine and biology: peptides and peptide-based biomaterials and their biomedical applications. Cham: Springer, 2017, 1030: 185-227. (2017-10-29)[2024-08-01]. .
117	GU S P. Applying machine learning algorithms for the analysis of biological sequences and medical records[D/OL]. Electronic Theses and Dissertations. Brookings: South Dakota State University, 2019, 3666[2024-08-01]. .
118	TRIPATHI N M, BANDYOPADHYAY A. High throughput virtual screening (HTVS) of peptide library: technological advancement in ligand discovery[J]. European Journal of Medicinal Chemistry, 2022, 243: 114766.
119	DANG Y, GUAN J J. Nanoparticle-based drug delivery systems for cancer therapy[J]. Smart Materials in Medicine, 2020, 1: 10-19.
26	MERRIFIELD R B. Solid phase peptide synthesis. Ⅰ. The synthesis of a tetrapeptide[J]. Journal of the American Chemical Society, 1963, 85(14): 2149-2154.
27	ABDILDINOVA D A, KURTH P M J, GONG P Y. Solid-phase synthesis of peptidomimetics with peptide backbone modifications[J]. Asian Journal of Organic Chemistry, 2021, 10(9): 2300-2317.
28	ZHANG R F, YAN H, WANG X J, et al. Screening of a short chain antimicrobial peptide - FWKFK and its application in wound healing[J]. Biomaterials Science, 2023, 11(5): 1867-1875.
29	SABANA I, NAUFAL M, WIANI I, et al. Synthesis of antioxidant peptide SCAP1 (Leu-Ala-Asn-Ala-Lys)[J]. Egyptian Journal of Chemistry, 2020, 63(3): 921-926.
30	BAHARLOUI M, MIRSHOKRAEE S A, MONFARED A, et al. Design and synthesis of novel triazole-based peptide analogues as anticancer agents[J]. Iranian Journal of Pharmaceutical Research, 2019, 18(3): 1299-1308.
31	WALEWSKA A, KOSIKOWSKA-ADAMUS P, TOMCZYKOWSKA M, et al. Improving fmoc solid phase synthesis of human beta defensin 3[J]. International Journal of Molecular Sciences, 2022, 23(20): 12562.
32	COLLINS J M, SINGH S K, WHITE T A, et al. Total wash elimination for solid phase peptide synthesis[J]. Nature Communications, 2023, 14(1): 8168.
33	BARREDO-VACCHELLI G R, RODRÍGUEZ J A, ELOY J A, et al. A novel method for liraglutide synthesis and purification[J]. Peptide Science, 2024, 116(5): e24351.
34	CHRISTOU G A, KATSIKI N, BLUNDELL J, et al. Semaglutide as a promising antiobesity drug[J]. Obesity Reviews, 2019, 20(6): 805-815.
35	PENG D Z, LI Y, SI L L, et al. A two-step method preparation of semaglutide through solid-phase synthesis and inclusion body expression[J]. Protein Expression and Purification, 2024, 219: 106477.
36	ANDRAOS J, MUHAR H, SMITH S R. Beyond glycemia: comparing tirzepatide to GLP-1 analogues[J]. Reviews in Endocrine & Metabolic Disorders, 2023, 24(6): 1089-1101.
37	FREDERICK M O, BOYSE R A, BRADEN T M, et al. Kilogram-scale GMP manufacture of tirzepatide using a hybrid SPPS/LPPS approach with continuous manufacturing[J]. Organic Process Research & Development, 2021, 25(7): 1628-1636.
38	ROSENSTOCK J, FRIAS J, JASTREBOFF A M, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA[J]. The Lancet, 2023, 402(10401): 529-544.
39	KENT S B H. Chemical synthesis of peptides and proteins[J]. Annual Review of Biochemistry, 1988, 57: 957-989.
40	DAWSON P E, MUIR T W, CLARK-LEWIS I, et al. Synthesis of proteins by native chemical ligation[J]. Science, 1994, 266(5186): 776-779.
41	TYMECKA D, MISICKA A. Solution phase peptide synthesis: the case of biphalin[M/OL]//HUSSEIN W M, SKWARCZYNSKI M, TOTH I. Peptide synthesis: peptide synthesis. New York, NY: Springer US, 2020: 1-11 [2024-10-15]. .
42	GU X T, CHEN W J, GUO T, et al. A novel synthetic method for backbone-cyclized polypeptide POL7080 with the help of hydrophobic-support materials[J]. Organic & Biomolecular Chemistry, 2024, 22(1): 85-89.
43	LI H D, WANG L J, ZHANG L Y, et al. Scalable preparation of green C-terminal amidation peptide-synthesis TAGs and the optimized TAG-assisted liquid-phase synthesis of eptifibatide[J]. Sustainable Chemistry and Pharmacy, 2024, 41: 101684.
44	蔡木易. 食源性低聚肽[M]. 北京: 中国轻工业出版社, 2021.
	CAI M Y. Food-derived oligopeptides[M]. Beijing: China Light Industry Press, 2021.
45	GU Y C, WU J P. LC-MS/MS coupled with QSAR modeling in characterising of angiotensin Ⅰ-converting enzyme inhibitory peptides from soybean proteins[J]. Food Chemistry, 2013, 141(3): 2682-2690.
46	SORNWATANA T, BANGPHOOMI K, ROYTRAKUL S, et al. Chebulin: Terminalia chebula Retz. fruit-derived peptide with angiotensin-Ⅰ-converting enzyme inhibitory activity[J]. Biotechnology and Applied Biochemistry, 2015, 62(6): 746-753.
47	WANG X M, CHEN H X, FU X G, et al. A novel antioxidant and ACE inhibitory peptide from rice bran protein: Biochemical characterization and molecular docking study[J]. LWT, 2017, 75: 93-99.
48	BABJI A S, DAUD N A, HUSAIN S G. Effect of molecular weight reduction of polypeptides on angiotensin converting enzyme (ACE) inhibitory activity in chicken skin hydrolysate (collagen)[J]. Journal of Nutritional Therapeutics, 2014, 3(2): 81-86.
49	RASLI H I, SARBON N M. Optimization of enzymatic hydrolysis conditions and characterization of Shortfin scad (Decapterus Macrosoma) skin gelatin hydrolysate sate using response surface methodology[J]. International Food Research Journal, 2018, 25(4): 1541-1549.
50	ZENG W C, ZHANG W H, HE Q, et al. Purification and characterization of a novel antioxidant peptide from bovine hair hydrolysates[J]. Process Biochemistry, 2015, 50(6): 948-954.
51	TAKAHASHI Y, KAMATA A, KONISHI T. Dipeptidyl peptidase-Ⅳ inhibitory peptides derived from salmon milt and their effects on postprandial blood glucose level[J]. Fisheries Science, 2021, 87(4): 619-626.
52	HENAUX L, PEREIRA K D, THIBODEAU J, et al. Glucoregulatory and anti-inflammatory activities of peptide fractions separated by electrodialysis with ultrafiltration membranes from salmon protein hydrolysate and identification of four novel glucoregulatory peptides[J]. Membranes, 2021, 11(7): 528.
53	CAI B N, WAN P, CHEN H, et al. Purification and identification of novel myeloperoxidase inhibitory antioxidant peptides from tuna (Thunnas albacares) protein hydrolysates[J]. Molecules, 2022, 27(9): 2681.
54	SINGH A, UTOMO PUTRI G A, MITTAL A, et al. Protein hydrolysate from splendid squid (Loligo formosana) fins: antioxidant, functional properties, and flavoring profile[J]. Turkish Journal of Fisheries and Aquatic Sciences, 2022, 22(6): TRJFAS21005.
55	KANNAN A, HETTIARACHCHY N S, MARSHALL M, et al. Shrimp shell peptide hydrolysates inhibit human cancer cell proliferation[J]. Journal of the Science of Food and Agriculture, 2011, 91(10): 1920-1924.
56	DE LA FUENTE B, PALLARÉS N, BERRADA H, et al. Salmon (Salmo salar) side streams as a bioresource to obtain potential antioxidant peptides after applying pressurized liquid extraction (PLE)[J]. Marine Drugs, 2021, 19(6): 323.
57	WANG B, LI L, CHI C F, et al. Purification and characterisation of a novel antioxidant peptide derived from blue mussel (Mytilus edulis) protein hydrolysate[J]. Food Chemistry, 2013, 138(2-3): 1713-1719.
58	KIM E K, KIM Y S, HWANG J W, et al. Purification of a novel nitric oxide inhibitory peptide derived from enzymatic hydrolysates of Mytilus coruscus [J]. Fish & Shellfish Immunology, 2013, 34(6): 1416-1420.
59	CHEN X L, PENG M, LI J, et al. Preparation and functional evaluation of collagen oligopeptide-rich hydrolysate from fish skin with the serine collagenolytic protease from Pseudoalteromonas sp. SM9913[J]. Scientific Reports, 2017, 7(1): 15716.
60	HERBEL V, SCHÄFER H, WINK M. Recombinant production of snakin-2 (an antimicrobial peptide from tomato) in E. coli and analysis of its bioactivity[J]. Molecules, 2015, 20(8): 14889-14901.
61	WU Y Y, MA Y K, LI L H, et al. Preparation and antioxidant activities in vitro of a designed antioxidant peptide from Pinctada fucata by recombinant Escherichia coli [J]. Journal of Microbiology and Biotechnology, 2018, 28(1): 1-11.
62	MOMEN A H, HARZANDI N, HADDADI A, et al. Implementation of a novel self-induced promoter for the expression of pharmaceutical peptides in Escherichia coli: YY_(3-36) peptide[J]. Hormone Molecular Biology and Clinical Investigation, 2020, 41(1): 20180056.
63	RAUNIYAR K, AKHONDZADEH S, GĄCIARZ A, et al. Bioactive VEGF-C from E. coli [J]. Scientific Reports, 2022, 12: 18157.
64	XIE H L, LI J, LI L, et al. Enhanced proliferation and differentiation of neural stem cells grown on PHA films coated with recombinant fusion proteins[J]. Acta Biomaterialia, 2013, 9(8): 7845-7854.
65	曹艳萍, 单安山, 马清泉, 等. 多拷贝策略在小肽表达中的应用[J]. 生物工程学报, 2011, 27(5): 684-689.
	CAO Y P, SHAN A S, MA Q Q, et al. Application of multi-copies in expression of smaller peptides: a review[J]. Chinese Journal of Biotechnology, 2011, 27(5): 684-689.
66	黄欣媛, 邹礼平, 范红波. 豆类活性肽PA1b在大肠杆菌中的多拷贝串联表达[J]. 江苏农业科学, 2022, 50(15): 57-62.
	HUANG X Y, ZOU L P, FAN H B. Prokaryotic expression of multicopies of legume peptide PA1b in Escherichia coli [J]. Jiangsu Agricultural Sciences, 2022, 50(15): 57-62.
67	ZHANG J X, MOVAHEDI A, WEI Z H, et al. High-level SUMO-mediated fusion expression of ABP-dHC-cecropin A from multiple joined genes in Escherichia coli [J]. Analytical Biochemistry, 2016, 509: 15-23.

分类	作用机制和典型氨基酸序列	特点和应用场景	参考文献
抗菌肽	①破坏细胞膜结构：通过与细菌细胞膜中的磷脂双层结合，增加膜通透性，导致细胞内容物泄漏，从而杀死细菌 ②抑制细菌代谢途径：干扰细菌DNA、RNA和蛋白质合成，抑制细菌生长和繁殖 ③典型氨基酸序列：Phe-Trp-Lys-Phe-Lys	广谱抗菌、抗感染，特别是对抗耐药性菌株感染有很好效果；促进伤口愈合；预防感染；治疗女性阴道念珠菌感染等	[3-4]
抗病毒肽	①阻断病毒进入细胞：通过与病毒外壳蛋白或宿主细胞受体结合，阻止病毒附着和进入宿主细胞 ②抑制病毒复制：干扰病毒RNA或DNA合成，从而抑制病毒复制 ③典型氨基酸序列：Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val--Leu-Leu-Ala-Leu-Leu-Ala-Pro	通过抑制病毒蛋白的功能，阻断病毒生命周期；可预防病毒感染，对于已感染病毒患者，则可阻止病毒在体内的进一步繁殖	[4,19]
抗氧化肽	①清除自由基：通过捐献电子或氢原子，中和体内自由基，减少自由基对细胞损伤 ②提高抗氧化酶活性：通过提高超氧化物歧化酶（superoxide dismutase, SOD）和过氧化氢酶等抗氧化酶的活性，增强机体抗氧化能力 ③典型氨基酸序列：Leu-Ala-Asn-Ala-Lys	安全性高，可以用在食品领域抗氧化上；也可开发相应抗氧化化妆品、保健食品或者药品	[5-9]
抗紫外肽	①吸收紫外线：通过吸收紫外线光子，减少其对皮肤的穿透和损伤 ②修复紫外线损伤：通过促进DNA修复机制，修复紫外线引起的DNA损伤，减少皮肤癌的发生 ③典型氨基酸序列：Leu-Val-Asn-Glu-Leu-Thr-Glu-Phe-Ala-Gln	增强皮肤对紫外线损伤的防御和修护能力以及防止光老化，在防晒护肤品中应用前景广阔	[10-11]
抗癌肽	①诱导细胞凋亡：通过激活凋亡信号通路，如Caspase级联反应，诱导癌细胞凋亡 ②抑制血管生成：通过抑制血管内皮生长因子（vascular endothelial growth factor, VEGF）活性，减少肿瘤血管生成，从而抑制肿瘤生长 ③典型氨基酸序列：Xxx-Arg-Gly-Asp-Xxx	肽易于人体吸收，可选择性地抑制肿瘤细胞生长，同时对正常细胞影响较小，亦可降低化疗药物毒副作用	[12-14,20]
免疫调节肽	①增强免疫细胞功能：促进T细胞、B细胞和自然杀伤细胞（natural killer cell, NK cell）的增殖和活化，提高免疫系统整体功能 ②调节细胞因子分泌：通过调节细胞因子分泌，平衡促炎和抗炎反应，维持免疫稳态 ③典型氨基酸序列：Gly-Arg-Gly-(Asp)₉	增强机体免疫反应或抑制过度免疫反应，达到免疫平衡效果，在调节免疫方面有良好的应用前景	[15]
美白肽	①抑制酪氨酸酶活性：美白肽通过与酪氨酸酶结合，抑制其活性，从而减少黑色素的合成 ②干扰黑色素转运：某些美白肽可干扰黑色素小体从黑素细胞向角质形成细胞的转运，减少皮肤色素沉着 ③典型氨基酸序列： H-Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val-NH₂	具有更好的安全性和美白活性，可在美白护肤品中广泛应用	[21-22]
减肥肽	①促进胰岛素分泌：胰高血糖素样肽-1受体激动剂（glucagon-like peptide-1 receptor agonists, GLP-1RA）可增加胰岛素分泌，降低血糖水平 ②抑制胰高血糖素分泌：GLP-1RA可减少胰高血糖素的分泌，减缓肝脏释放葡萄糖 ③延缓胃排空：GLP-1RA能延缓胃排空速度，使饭后血糖上升更为温和 ④减少食欲：GLP-1RA可降低食欲 ⑤典型氨基酸序列：His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly	GLP-1RA不仅能够良好安全地控制血糖水平，适用于2型糖尿病患者的血糖控制；而且能有效减少热量摄入，帮助控制体重，达到有效减肥效果	[23-24]

分类	作用机制和典型氨基酸序列	特点和应用场景	参考文献
抗菌肽	①破坏细胞膜结构：通过与细菌细胞膜中的磷脂双层结合，增加膜通透性，导致细胞内容物泄漏，从而杀死细菌 ②抑制细菌代谢途径：干扰细菌DNA、RNA和蛋白质合成，抑制细菌生长和繁殖 ③典型氨基酸序列：Phe-Trp-Lys-Phe-Lys	广谱抗菌、抗感染，特别是对抗耐药性菌株感染有很好效果；促进伤口愈合；预防感染；治疗女性阴道念珠菌感染等	[3-4]
抗病毒肽	①阻断病毒进入细胞：通过与病毒外壳蛋白或宿主细胞受体结合，阻止病毒附着和进入宿主细胞 ②抑制病毒复制：干扰病毒RNA或DNA合成，从而抑制病毒复制 ③典型氨基酸序列：Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val--Leu-Leu-Ala-Leu-Leu-Ala-Pro	通过抑制病毒蛋白的功能，阻断病毒生命周期；可预防病毒感染，对于已感染病毒患者，则可阻止病毒在体内的进一步繁殖	[4,19]
抗氧化肽	①清除自由基：通过捐献电子或氢原子，中和体内自由基，减少自由基对细胞损伤 ②提高抗氧化酶活性：通过提高超氧化物歧化酶（superoxide dismutase, SOD）和过氧化氢酶等抗氧化酶的活性，增强机体抗氧化能力 ③典型氨基酸序列：Leu-Ala-Asn-Ala-Lys	安全性高，可以用在食品领域抗氧化上；也可开发相应抗氧化化妆品、保健食品或者药品	[5-9]
抗紫外肽	①吸收紫外线：通过吸收紫外线光子，减少其对皮肤的穿透和损伤 ②修复紫外线损伤：通过促进DNA修复机制，修复紫外线引起的DNA损伤，减少皮肤癌的发生 ③典型氨基酸序列：Leu-Val-Asn-Glu-Leu-Thr-Glu-Phe-Ala-Gln	增强皮肤对紫外线损伤的防御和修护能力以及防止光老化，在防晒护肤品中应用前景广阔	[10-11]
抗癌肽	①诱导细胞凋亡：通过激活凋亡信号通路，如Caspase级联反应，诱导癌细胞凋亡 ②抑制血管生成：通过抑制血管内皮生长因子（vascular endothelial growth factor, VEGF）活性，减少肿瘤血管生成，从而抑制肿瘤生长 ③典型氨基酸序列：Xxx-Arg-Gly-Asp-Xxx	肽易于人体吸收，可选择性地抑制肿瘤细胞生长，同时对正常细胞影响较小，亦可降低化疗药物毒副作用	[12-14,20]
免疫调节肽	①增强免疫细胞功能：促进T细胞、B细胞和自然杀伤细胞（natural killer cell, NK cell）的增殖和活化，提高免疫系统整体功能 ②调节细胞因子分泌：通过调节细胞因子分泌，平衡促炎和抗炎反应，维持免疫稳态 ③典型氨基酸序列：Gly-Arg-Gly-(Asp)₉	增强机体免疫反应或抑制过度免疫反应，达到免疫平衡效果，在调节免疫方面有良好的应用前景	[15]
美白肽	①抑制酪氨酸酶活性：美白肽通过与酪氨酸酶结合，抑制其活性，从而减少黑色素的合成 ②干扰黑色素转运：某些美白肽可干扰黑色素小体从黑素细胞向角质形成细胞的转运，减少皮肤色素沉着 ③典型氨基酸序列： H-Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val-NH₂	具有更好的安全性和美白活性，可在美白护肤品中广泛应用	[21-22]
减肥肽	①促进胰岛素分泌：胰高血糖素样肽-1受体激动剂（glucagon-like peptide-1 receptor agonists, GLP-1RA）可增加胰岛素分泌，降低血糖水平 ②抑制胰高血糖素分泌：GLP-1RA可减少胰高血糖素的分泌，减缓肝脏释放葡萄糖 ③延缓胃排空：GLP-1RA能延缓胃排空速度，使饭后血糖上升更为温和 ④减少食欲：GLP-1RA可降低食欲 ⑤典型氨基酸序列：His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly	GLP-1RA不仅能够良好安全地控制血糖水平，适用于2型糖尿病患者的血糖控制；而且能有效减少热量摄入，帮助控制体重，达到有效减肥效果	[23-24]

对比维度	固相合成法（SPPS）	液相合成法（LPPS）
原理与过程	固相载体上逐步缩合氨基酸	溶液中氨基酸/肽片段进行耦合
自动化程度	高，流程化的操作可以通过自动化的多肽合成设备实现自动化生产	较低，操作过程较为复杂，目前难以实现大规模自动化生产
适用范围	中长链多肽（通常40个氨基酸以内）	短肽及特定结构要求的多肽（通常10个氨基酸以内）
产率	较高，随着肽链延长收率下降	适中，随着肽链延长收率迅速下降
纯度	较高，随着肽链延长纯度下降	适中，随着肽链延长纯度迅速下降
耗时	较长，每个氨基酸通常需2～3 h	适中，合成简洁迅速
成本	较高，树脂和大量溶剂	相对较低

对比维度	固相合成法（SPPS）	液相合成法（LPPS）
原理与过程	固相载体上逐步缩合氨基酸	溶液中氨基酸/肽片段进行耦合
自动化程度	高，流程化的操作可以通过自动化的多肽合成设备实现自动化生产	较低，操作过程较为复杂，目前难以实现大规模自动化生产
适用范围	中长链多肽（通常40个氨基酸以内）	短肽及特定结构要求的多肽（通常10个氨基酸以内）
产率	较高，随着肽链延长收率下降	适中，随着肽链延长收率迅速下降
纯度	较高，随着肽链延长纯度下降	适中，随着肽链延长纯度迅速下降
耗时	较长，每个氨基酸通常需2～3 h	适中，合成简洁迅速
成本	较高，树脂和大量溶剂	相对较低

名称	原料	蛋白酶种类	酶解条件	分离纯化	功能描述	参考文献
降压肽	大豆蛋白	嗜热菌蛋白酶、胃蛋白酶、胰蛋白酶	50 g/L，55 °C，pH 8, 3 h；37 °C，pH 8, 3 h； 37 °C，pH 7.6，3 h	离心、LC-MS	ACE抑制活性	[45]
降压肽	诃子果实	胃蛋白酶	1∶25(质量比)，37°C，12 h	离心、RP-HPLC	ACE抑制活性	[46]
降压肽	米糠	胰蛋白酶	50 mg/mL，1500 U/mg，37 °C，pH 8，2 h	离心	ACE抑制活性、抗氧化	[47]
降压肽	鸡皮	碱性蛋白酶	10 g/L，60 °C，pH 9.5，4 h	离心、超滤	ACE抑制活性	[48]
降压肽	短鳍鱼	碱性蛋白酶	10 g/L	离心、过滤	ACE抑制活性	[49]
抗氧化肽	牛毛	碱性蛋白酶	5%，55 °C，8 h	离心、凝胶过滤、分子排阻色谱	抗氧化	[50]
二肽酶抑制肽	三文鱼鱼白	蜂蜜曲霉蛋白酶	5种蛋白酶筛选，50 °C， >5 h，17.5 g酶/7.2 kg原料	硅藻土过滤、超滤、浓缩	控制血糖	[51]
血糖控制以及抗炎肽	去骨三文鱼	胃蛋白酶、胰蛋白酶、胰凝乳蛋白酶	NA	过滤、超滤	控制血糖、抗炎	[52]
抗氧化肽	黄鳍金枪鱼	碱性蛋白酶	酶量3000 U/g，50 °C，5 h，100 r/min	离心、超滤Sephadex G-15	抗氧化	[53]
抗氧化肽	鱿鱼	碱性蛋白酶	酶量5～30 U/g，5～180 min	离心	抗氧化	[54]
抗癌肽	虾壳	Cryotin酶	pH 8，50 °C，45 min	离心、超滤	抗恶性细胞增殖	[55]

功能肽合成和挖掘策略研究进展

Advances in synthesis and mining strategies for functional peptides

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 67

相关文章 15

编辑推荐

Metrics

本文评价

表达系统	优势	不足	应用范围	产业化现状
大肠杆菌	繁殖速度快、培养周期短、遗传背景清晰、工艺放大技术成熟、成本低	易形成包涵体、存在内毒素风险	抗菌肽、抗氧化肽、减肥肽、化妆品肽等	技术成熟，可实现产业化放大
枯草芽孢杆菌	遗传背景清晰、安全性强、可分泌表达至培养基中、纯化简单	表达量偏低、重组质粒易丢失	淀粉酶、蛋白酶、维生素等	技术成熟，产业化程度较低
酵母菌	一定的翻译后修饰、耐受能力强	发酵周期长、表达量不高	抗菌肽、免疫调节肽等	技术成熟，可实现产业化放大

[1]	盛周煌, 陈智仙, 张彦. 酵母甘露糖蛋白的研究进展[J]. 合成生物学, 2025, 6(2): 408-421.
[2]	张梦瑶, 蔡鹏, 周雍进. 合成生物学助力萜类香精香料可持续生产[J]. 合成生物学, 2025, 6(2): 334-356.
[3]	张璐鸥, 徐丽, 胡晓旭, 杨滢. 合成生物学助力化妆品走进生物制造新时代[J]. 合成生物学, 2025, 6(2): 479-491.
[4]	鲁锦畅, 武耀康, 吕雪芹, 刘龙, 陈坚, 刘延峰. 神经酰胺类鞘脂的绿色生物制造[J]. 合成生物学, 2025, 6(2): 422-444.
[5]	伊进行, 唐宇琳, 李春雨, 吴鹤云, 马倩, 谢希贤. 氨基酸衍生物在化妆品中的应用及其生物合成研究进展[J]. 合成生物学, 2025, 6(2): 254-289.
[6]	韦灵珍, 王佳, 孙新晓, 袁其朋, 申晓林. 黄酮类化合物生物合成及其在化妆品中应用的研究[J]. 合成生物学, 2025, 6(2): 373-390.
[7]	肖森, 胡立涛, 石智诚, 王发银, 余思婷, 堵国成, 陈坚, 康振. 可控分子量透明质酸的生物合成研究进展[J]. 合成生物学, 2025, 6(2): 445-460.
[8]	王倩, 果士婷, 辛波, 钟成, 王钰. L-精氨酸的微生物合成研究进展[J]. 合成生物学, 2025, 6(2): 290-305.
[9]	左一萌, 张姣姣, 连佳长. 酿酒酵母使能技术在化妆品原料合成中的应用[J]. 合成生物学, 2025, 6(2): 233-253.
[10]	郭婷婷, 韩湘凝, 黄熙婷, 张婷婷, 孔健. 乳酸菌的合成生物学工具及在合成益肤因子中的应用[J]. 合成生物学, 2025, 6(2): 320-333.
[11]	张萍, 张维娇, 胥睿睿, 李江华, 陈坚, 康振. 防晒化合物类菌孢素氨基酸的生物合成[J]. 合成生物学, 2025, 6(2): 306-319.
[12]	黄姝涵, 马赫, 罗云孜. 生物合成红景天苷的研究进展[J]. 合成生物学, 2025, 6(2): 391-407.
[13]	高歌, 边旗, 王宝俊. 合成基因线路的工程化设计研究进展与展望[J]. 合成生物学, 2025, 6(1): 45-64.
[14]	李冀渊, 吴国盛. 合成生物学视域下有机体的两种隐喻[J]. 合成生物学, 2025, 6(1): 190-202.
[15]	焦洪涛, 齐蒙, 邵滨, 蒋劲松. DNA数据存储技术的法律治理议题[J]. 合成生物学, 2025, 6(1): 177-189.