科微学术

生物工程学报

2025年6月18日 4:59 星期三
首页 > 过刊浏览>2024年第40卷第12期 >4396-4407. DOI:10.13345/j.cjb.240077
PDF HTML阅读 XML下载 导出引用 引用提醒
抗酶解抗菌肽的研究进展
作者:
基金项目:

中国博士后科学基金(2022M720694);黑龙江省自然科学基金优秀青年项目(YQ2022C015);黑龙江省博士后资助项目(LBH-Z22007);黑龙江省高校协同创新成果项目(LJGXCG2022-022)


Research progress in anti-enzymatic antimicrobial peptides
Author:
  • 摘要
    • | |
  • 访问统计
    • |
  • 参考文献 [75]
    • |
  • 相似文献 [20]
    • | | |
  • 文章评论
    摘要:

    抗菌肽(antimicrobial peptides, AMPs)是机体先天免疫中的一类小分子多肽，作为机体防御的第一道防线，在自然界中广泛存在。AMPs具有多种生物学活性且不易产生耐药性，但天然AMPs容易被体内的各种消化酶降解。在AMPs中引入非天然氨基酸、化学修饰、合理规避酶切位点进行氨基酸重排、肽的环化、纳米肽设计等提高AMPs蛋白酶稳定的方法不断出现。本文重点综述了提高AMPs蛋白酶稳定性的各种方法，以期为此领域的研究提供参考。

    Abstract:

    Antimicrobial peptides (AMPs) are small molecular peptides widely existing in the innate immunity of organisms, serving as the first line of defense. Natural AMPs possess various biological activities and are difficult to develop drug resistance. However, they are easily broken down by digestive enzymes in the body. In recent years, increasing methods have been reported to enhance the stability of AMPs, including incorporation of unnatural amino acids, chemical modifications, strategic avoidance of enzyme cleavage sites, cyclization, and nano peptide design. This review summarizes the methods for improving the stability of AMPs against protease degradation, aiming to provide references for further research in this field.

    参考文献
    [1] MAGANA M, PUSHPANATHAN M, SANTOS AL, LEANSE L, FERNANDEZ M, IOANNIDIS A, GIULIANOTTI MA, APIDIANAKIS Y, BRADFUTE S, FERGUSON AL, CHERKASOV A, SELEEM MN, PINILLA C, DE LA FUENTE-NUNEZ C, LAZARIDIS T, DAI TH, HOUGHTEN RA, HANCOCK REW, TEGOS GP. The value of antimicrobial peptides in the age of resistance[J]. The Lancet Infectious Diseases, 2020, 20(9): e216-e230.
    [2] SHAO CX, TIAN HT, WANG TY, WANG ZH, CHOU SL, SHAN AS, CHENG BJ. Central β-turn increases the cell selectivity of imperfectly amphipathic α-helical peptides[J]. Acta Biomaterialia, 2018, 69: 243-255.
    [3] WANG JJ, CHOU SL, YANG ZY, YANG Y, WANG ZH, SONG J, DOU XJ, SHAN AS. Combating drug-resistant fungi with novel imperfectly amphipathic palindromic peptides[J]. Journal of Medicinal Chemistry, 2018, 61(9): 3889-3907.
    [4] CHEN RN, MAO YM, WANG J, LIU M, QIAO Y, ZHENG LB, SU YQ, KE QZ, ZHENG WQ. Molecular mechanisms of an antimicrobial peptide piscidin (lc-pis) in a parasitic protozoan, cryptocaryon irritans[J]. BMC Genomics, 2018, 19(1): 192.
    [5] GUI L, ZHANG PP, ZHANG QY, ZHANG JB. Two hepcidins from spotted scat (Scatophagus argus) possess antibacterial and antiviral functions in vitro[J]. Fish & Shellfish Immunology, 2016, 50: 191-199.
    [6] 姜宇, 李秀, 林瑛. 利用ELP-Intein系统在大肠杆菌中生产抗菌肽DLP4[J]. 生物工程学报, 2022, 38(6): 2365-2376.JIANG Y, LI X, LIN Y. Production of antimicrobial peptide DLP4 in Escherichia coli using an ELP-Intein system[J]. Chinese Journal of Biotechnology, 2022, 38(6): 2365-2376(in Chinese).
    [7] LYU YF, YANG Y, LYU XT, DONG N, SHAN AS. Antimicrobial activity, improved cell selectivity and mode of action of short pmap-36-derived peptides against bacteria and candida[J]. Scientific Reports, 2016, 6: 27258.
    [8] MA Z, WEI DD, YAN P, ZHU X, SHAN AS, BI ZP. Characterization of cell selectivity, physiological stability and endotoxin neutralization capabilities of α-helix-based peptide amphiphiles[J]. Biomaterials, 2015, 52: 517-530.
    [9] ECKERT R. Road to clinical efficacy: challenges and novel strategies for antimicrobial peptide development[J]. Future Microbiology, 2011, 6(6): 635-651.
    [10] PESCHEL A, SAHL HG. The co-evolution of host cationic antimicrobial peptides and microbial resistance[J]. Nature Reviews Microbiology, 2006, 4: 529-536.
    [11] ONG ZY, WIRADHARMA N, YANG YY. Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials[J]. Advanced Drug Delivery Reviews, 2014, 78: 28-45.
    [12] CARMONA G, RODRIGUEZ A, JUAREZ D, CORZO G, VILLEGAS E. Improved protease stability of the antimicrobial peptide pin2 substituted with d-amino acids[J]. The Protein Journal, 2013, 32(6): 456-466.
    [13] PAPO N, OREN Z, PAG U, SAHL HG, SHAI Y. The consequence of sequence alteration of an amphipathic alpha-helical antimicrobial peptide and its diastereomers[J]. The Journal of Biological Chemistry, 2002, 277(37): 33913-33921.
    [14] DEWANGAN RP, BISHT GS, SINGH VP, YAR MS, PASHA S. Design and synthesis of cell selective α/β-diastereomeric peptidomimetic with potent in vivo antibacterial activity against methicillin resistant S. aureus[J]. Bioorganic Chemistry, 2018, 76: 538-547.
    [15] DE LUCIO H, GAMO AM, RUIZ-SANTAQUITERIA M, DE CASTRO S, SÁNCHEZ-MURCIA PA, TORO MA, GUTIÉRREZ KJ, GAGO F, JIMÉNEZ-RUIZ A, CAMARASA MJ, VELÁZQUEZ S. Improved proteolytic stability and potent activity against Leishmania infantum trypanothione reductase of α/β-peptide foldamers conjugated to cell-penetrating peptides[J]. European Journal of Medicinal Chemistry, 2017, 140: 615-623.
    [16] HE SQ, YANG ZY, LI XF, WU H, ZHANG LC, WANG JJ, SHAN AS. Optimized proteolytic resistance motif (DabW)-based U1-2WD: a membrane-induced self-aggregating peptide to trigger bacterial agglutination and death[J]. Acta Biomaterialia, 2022, 153: 540-556.
    [17] KNAPPE D, HENKLEIN P, HOFFMANN R, HILPERT K. Easy strategy to protect antimicrobial peptides from fast degradation in serum[J]. Antimicrobial Agents and Chemotherapy, 2010, 54(9): 4003-4005.
    [18] HE SQ, YANG ZY, LI XF, WU H, ZHANG LC, SHAN AS, WANG JJ. Boosting stability and therapeutic potential of proteolysis-resistant antimicrobial peptides by end-tagging β-naphthylalanine[J]. Acta Biomaterialia, 2023, 164: 175-194.
    [19] DE ZOTTI M, BIONDI B, PEGGION C, PARK Y, HAHM KS, FORMAGGIO F, TONIOLO C. Synthesis, preferred conformation, protease stability, and membrane activity of heptaibin, a medium-length peptaibiotic[J]. Journal of Peptide Science: an Official Publication of the European Peptide Society, 2011, 17(8): 585-594.
    [20] NGUYEN HH, IMHOF D, KRONEN M, SCHLEGEL B, HÄRTL A, GRÄFE U, GERA L, REISSMANN S. Synthesis and biological evaluation of analogues of the peptaibol ampullosporin A[J]. Journal of Medicinal Chemistry, 2002, 45(13): 2781-2787.
    [21] YAMAGUCHI H, KODAMA H, OSADA S, KATO F, JELOKHANI-NIARAKI M, KONDO M. Effect of alpha, alpha-dialkyl amino acids on the protease resistance of peptides[J]. Bioscience, Biotechnology, and Biochemistry, 2003, 67(10): 2269-2272.
    [22] SADOWSKY JD, MURRAY JK, TOMITA Y, GELLMAN SH. Exploration of backbone space in foldamers containing alpha- and beta-amino acid residues: developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL[J]. Chembiochem: a European Journal of Chemical Biology, 2007, 8(8): 903-916.
    [23] DE ZOTTI M, BIONDI B, FORMAGGIO F, TONIOLO C, STELLA L, PARK Y, HAHM KS. Trichogin GA IV: an antibacterial and protease-resistant peptide[J]. Journal of Peptide Science: an Official Publication of the European Peptide Society, 2009, 15(9): 615-619.
    [24] KARLE IL, BALARAM P. Structural characteristics of alpha-helical peptide molecules containing Aib residues[J]. Biochemistry, 1990, 29(29): 6747-6756.
    [25] DI BLASIO B, PAVONE V, SAVIANO M, LOMBARDI A, NASTRI F, PEDONE C, BENEDETTI E, CRISMA M, ANZOLIN M, TONIOLO C. Structural characterization of the.beta.-bend ribbon spiral: crystallographic analysis of two long (l-Pro-Aib)n sequential peptides[J]. Journal of the American Chemical Society, 1992, 114(16): 6273-6278.
    [26] TONIOLO C, CRISMA M, FORMAGGIO F, PEGGION C. Control of peptide conformation by the Thorpe-Ingold effect (C alpha-tetrasubstitution)[J]. Biopolymers, 2001, 60(6): 396-419.
    [27] SANTOS JHPM, TORRES-OBREQUE KM, MENEGUETTI GP, AMARO BP, RANGEL-YAGUI CO. Protein pegylation for the design of biobetters: From reaction to purification processes[J]. Brazilian Journal of Pharmaceutical Sciences, 2018, 54: e01009.
    [28] MOREIRA BRITO JC, CARVALHO LR, NEVES DE SOUZA A, CARNEIRO G, MAGALHÃES PP, FARIAS LM, GUIMARÃES NR, VERLY RM, RESENDE JM, ELENA DE LIMA M. PEGylation of the antimicrobial peptide LyeTx I-b maintains structure-related biological properties and improves selectivity[J]. Frontiers in Molecular Biosciences, 2022, 9: 1001508.
    [29] FALCIANI C, LOZZI L, SCALI S, BRUNETTI J, BRACCI L, PINI A. Site-specific pegylation of an antimicrobial peptide increases resistance to Pseudomonas aeruginosa elastase[J]. Amino Acids, 2014, 46(5): 1403-1407.
    [30] ZHOU J, XU W, LIU ZZ, WANG C, XIA S, LAN QS, CAI YX, SU S, PU J, XING LX, XIE YH, LU L, JIANG SB, WANG Q. A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases[J]. Acta Pharmaceutica Sinica B, 2022, 12(4): 1652-1661.
    [31] TAN P, LAI ZH, JIAN Q, SHAO CX, ZHU YJ, LI GY, SHAN AS. Design of heptad repeat amphiphiles based on database filtering and structure-function relationships to combat drug-resistant fungi and biofilms[J]. ACS Applied Materials & Interfaces, 2020, 12(2): 2129-2144.
    [32] NGUYEN LT, CHAU JK, PERRY NA, DE BOER L, ZAAT SAJ, VOGEL HJ. Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs[J]. PLoS One, 2010, 5(9): e12684.
    [33] LI DD, YANG YH, LI RF, HUANG L, WANG ZC, DENG QW, DONG SB. N-terminal acetylation of antimicrobial peptide L163 improves its stability against protease degradation[J]. Journal of Peptide Science: an Official Publication of the European Peptide Society, 2021, 27(9): e3337.
    [34] STRÖMSTEDT AA, PASUPULETI M, SCHMIDTCHEN A, MALMSTEN M. Evaluation of strategies for improving proteolytic resistance of antimicrobial peptides by using variants of EFK17, an internal segment of LL-37[J]. Antimicrobial Agents and Chemotherapy, 2009, 53(2): 593-602.
    [35] HAUSCH F, SHAN L, SANTIAGO NA, GRAY GM, KHOSLA C. Intestinal digestive resistance of immunodominant gliadin peptides[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2002, 283(4): G996-G1003.
    [36] LI WY, SEPAROVIC F, O’BRIEN-SIMPSON NM, WADE JD. Chemically modified and conjugated antimicrobial peptides against superbugs[J]. Chemical Society Reviews, 2021, 50(8): 4932-4973.
    [37] HUANG W, GROOTHUYS S, HEREDIA A, KUIJPERS BHM, RUTJES FPJT, van DELFT FL, WANG LX. Enzymatic glycosylation of triazole-linked GlcNAc/Glc-peptides: synthesis, stability and anti-HIV activity of triazole-linked HIV-1 gp41 glycopeptide C34 analogues[J]. Chembiochem: a European Journal of Chemical Biology, 2009, 10(7): 1234-1242.
    [38] TORTORELLA A, LEONE L, LOMBARDI A, PIZZO E, BOSSO A, WINTER R, PETRACCONE L, DEL VECCHIO P, OLIVA R. The impact of n-glycosylation on the properties of the antimicrobial peptide LL-III[J]. Scientific Reports, 2023, 13(1): 3733.
    [39] DWIVEDI R, AGGARWAL P, BHAVESH NS, KAUR KJ. Design of therapeutically improved analogue of the antimicrobial peptide, indolicidin, using a glycosylation strategy[J]. Amino Acids, 2019, 51(10): 1443-1460.
    [40] ZHONG C, ZHU NY, ZHU YW, LIU TQ, GOU SH, XIE JQ, YAO J, NI JM. Antimicrobial peptides conjugated with fatty acids on the side chain of d-amino acid promises antimicrobial potency against multidrug-resistant bacteria[J]. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 2020, 141: 105123.
    [41] HUANG S, SU GQ, JIANG S, CHEN L, HUANG JX, YANG FY. New N-terminal fatty-acid-modified melittin analogs with potent biological activity[J]. International Journal of Molecular Sciences, 2024, 25(2): 867.
    [42] KIM H, JANG JH, KIM SC, CHO JH. De novo generation of short antimicrobial peptides with enhanced stability and cell specificity[J]. Journal of Antimicrobial Chemotherapy, 2014, 69(1): 121-132.
    [43] CRAIK CS, LARGMAN C, FLETCHER T, ROCZNIAK S, BARR PJ, FLETTERICK R, RUTTER WJ. Redesigning trypsin: alteration of substrate specificity[J]. Science, 1985, 228(4697): 291-297.
    [44] HARRIS JL, BACKES BJ, LEONETTI F, MAHRUS S, ELLMAN JA, CRAIK CS. Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries[J]. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97(14): 7754-7759.
    [45] WANG JJ, SONG J, YANG ZY, HE SQ, YANG Y, FENG XJ, DOU XJ, SHAN AS. Antimicrobial peptides with high proteolytic resistance for combating Gram-negative bacteria[J]. Journal of Medicinal Chemistry, 2019, 62(5): 2286-2304.
    [46] ZHU YJ, SHAO CX, LI GY, LAI ZH, TAN P, JIAN Q, CHENG BJ, SHAN AS. Rational avoidance of protease cleavage sites and symmetrical end-tagging significantly enhances the stability and therapeutic potential of antimicrobial peptides[J]. Journal of Medicinal Chemistry, 2020, 63(17): 9421-9435.
    [47] SHAO CX, ZHU YJ, LAI ZH, TAN P, SHAN AS. Antimicrobial peptides with protease stability: progress and perspective[J]. Future Medicinal Chemistry, 2019, 11(16): 2047-2050.
    [48] LOURENÇO ALP, RIOS TB, DA SILVA ÁP, FRANCO OL, RAMADA MHS. Peptide stapling applied to antimicrobial peptides[J]. Antibiotics, 2023, 12(9): 1400.
    [49] GUNASEKERA S, MUHAMMAD T, STRÖMSTEDT AA, ROSENGREN KJ, GÖRANSSON U. Backbone cyclization and dimerization of LL-37-derived peptides enhance antimicrobial activity and proteolytic stability[J]. Frontiers in Microbiology, 2020, 11: 168.
    [50] ZHAO JS, GE G, HUANG YB, HOU Y, HU SQ. Butelase 1-mediated enzymatic cyclization of antimicrobial peptides: improvements on stability and bioactivity[J]. Journal of Agricultural and Food Chemistry, 2022, 70(50): 15869-15878.
    [51] NEHLS C, BÖHLING A, PODSCHUN R, SCHUBERT S, GRÖTZINGER J, SCHROMM A, FEDDERS H, LEIPPE M, HARDER J, KACONIS Y, GRONOW S, GUTSMANN T. Influence of disulfide bonds in human beta defensin-3 on its strain specific activity against Gram-negative bacteria[J]. Biochimica et Biophysica Acta Biomembranes, 2020, 1862(8): 183273.
    [52] DOLLE A, NAGATI VB, HUNASHAL Y, KRISHNAMURTHY K, PASUPULATI AK, RAGHOTHAMA S, GOWD KH. Disulfide engineering on temporin-SHf: stabilizing the bioactive conformation of an ultra-short antimicrobial peptide[J]. Chemical Biology & Drug Design, 2019, 94(3): 1634-1646.
    [53] LUCKETT S, GARCIA RS, BARKER JJ, KONAREV AV, SHEWRY PR, CLARKE AR, BRADY RL. High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds[J]. Journal of Molecular Biology, 1999, 290(2): 525-533.
    [54] KORSINCZKY MLJ, SCHIRRA HJ, CRAIK DJ. Sunflower trypsin inhibitor-1[J]. Current Protein & Peptide Science, 2004, 5(5): 351-364.
    [55] WANG CS, SHAO CX, FANG YX, WANG JJ, DONG N, SHAN AS. Binding loop of sunflower trypsin inhibitor 1 serves as a design motif for proteolysis-resistant antimicrobial peptides[J]. Acta Biomaterialia, 2021, 124: 254-269.
    [56] KOEHBACH J, GANI J, HILPERT K, CRAIK DJ. Comparison of a short linear antimicrobial peptide with its disulfide-cyclized and cyclotide-grafted variants against clinically relevant pathogens[J]. Microorganisms, 2021, 9(6): 1249.
    [57] JING XS, JIN K. A gold mine for drug discovery: strategies to develop cyclic peptides into therapies[J]. Medicinal Research Reviews, 2020, 40(2): 753-810.
    [58] SHAO CX, JIAN Q, LI BW, ZHU YJ, YU WK, LI ZY, SHAN AS. Ultrashort all-hydrocarbon stapled α-helix amphiphile as a potent and stable antimicrobial compound[J]. Journal of Medicinal Chemistry, 2023, 66(16): 11414-11427.
    [59] ZENG ZZ, ZHU JB, DENG XY, CHEN HW, JIN Y, MICLET E, ALEZRA V, WAN Y. Customized reversible stapling for selective delivery of bioactive peptides[J]. Journal of the American Chemical Society, 2022, 144(51): 23614-23621.
    [60] LUONG HX, KIM DH, LEE BJ, KIM YW. Antimicrobial activity and stability of stapled helices of polybia-MP1[J]. Archives of Pharmacal Research, 2017, 40(12): 1414-1419.
    [61] YOU YH, LIU HY, ZHU YZ, ZHENG H. Rational design of stapled antimicrobial peptides[J]. Amino Acids, 2023, 55(4): 421-442.
    [62] HIRANO M, SAITO C, YOKOO H, GOTO C, KAWANO R, MISAWA T, DEMIZU Y. Development of antimicrobial stapled peptides based on Magainin 2 sequence[J]. Molecules, 2021, 26(2): 444.
    [63] WHITESIDES GM, GRZYBOWSKI B. Self-assembly at all scales[J]. Science, 2002, 295(5564): 2418-2421.
    [64] ZHANG SG. Fabrication of novel biomaterials through molecular self-assembly[J]. Nature Biotechnology, 2003, 21: 1171-1178.
    [65] GAZIT E. Molecular self-assembly: searching sequence space[J]. Nature Chemistry, 2015, 7(1): 14-15.
    [66] HAN ZB, FENG DM, WANG WX, WANG Y, CHENG MS, YANG HL, LIU Y. Influence of fatty acid modification on the anticancer activity of the antimicrobial peptide figainin 1[J]. ACS Omega, 2023, 8(44): 41876-41884.
    [67] LAI ZH, JIAN Q, LI GY, SHAO CX, ZHU YJ, YUAN XJ, CHEN HY, SHAN AS. Self-assembling peptide dendron nanoparticles with high stability and a multimodal antimicrobial mechanism of action[J]. ACS Nano, 2021, 15(10): 15824-15840.
    [68] LIU TQ, ZHU NY, ZHONG C, ZHU YW, GOU SH, CHANG LL, BAO HX, LIU H, ZHANG Y, NI JM. Effect of N-methylated and fatty acid conjugation on analogs of antimicrobial peptide Anoplin[J]. European Journal of Pharmaceutical Sciences, 2020, 152: 105453.
    [69] CHU-KUNG AF, NGUYEN R, BOZZELLI KN, TIRRELL M. Chain length dependence of antimicrobial peptide-fatty acid conjugate activity[J]. Journal of Colloid and Interface Science, 2010, 345(2): 160-167.
    [70] YU WK, WANG JJ, WANG ZH, LI LX, LI WY, SONG J, ZHANG SS, SHAN AS. PEGylation of the antimicrobial peptide PG-1: a link between propensity for nanostructuring and capacity of the antitrypsin hydrolytic ability[J]. Journal of Medicinal Chemistry, 2021, 64(14): 10469-10481.
    [71] ZHOU XR, CAO YM, ZHANG Q, TIAN XB, DONG H, CHEN L, LUO SZ. Self-assembly nanostructure controlled sustained release, activity and stability of peptide drugs[J]. International Journal of Pharmaceutics, 2017, 528(1-2): 723-731.
    [72] CHEN L, TU ZG, VOLOSHCHUK N, LIANG JF. Lytic peptides with improved stability and selectivity designed for cancer treatment[J]. Journal of Pharmaceutical Sciences, 2012, 101(4): 1508-1517.
    [73] TIAN XB, SUN FD, ZHOU XR, LUO SZ, CHEN L. Role of peptide self-assembly in antimicrobial peptides[J]. Journal of Peptide Science, 2015, 21(7): 530-539.
    [74] WADHWANI P, HEIDENREICH N, PODEYN B, BÜRCK J, ULRICH AS. Antibiotic gold: tethering of antimicrobial peptides to gold nanoparticles maintains conformational flexibility of peptides and improves trypsin susceptibility[J]. Biomaterials Science, 2017, 5(4): 817-827.
    [75] MARAMING P, DADUANG J, KAH JCY. Conjugation with gold nanoparticles improves the stability of the KT2 peptide and maintains its anticancer properties[J]. RSC Advances, 2022, 12(1): 319-325.
    引证文献
    网友评论
    网友评论
    分享到微博
    发 布
引用本文

邵长轩,王梦成,王袁梦雪,何诗琪,朱永杰,单安山. 抗酶解抗菌肽的研究进展[J]. 生物工程学报, 2024, 40(12): 4396-4407

复制
分享
文章指标
  • 点击次数:351
  • 下载次数: 258
  • HTML阅读次数: 245
  • 引用次数: 0
历史
  • 收稿日期:2024-01-26
  • 在线发布日期: 2024-12-25
  • 出版日期: 2024-12-25
文章二维码
您是第6525352位访问者
生物工程学报 ® 2025 版权所有

通信地址：中国科学院微生物研究所    邮编：100101

电话：010-64807509   E-mail：cjb@im.ac.cn

技术支持：北京勤云科技发展有限公司