摘要
阳离子抗菌肽是一类小分子多肽,具有抗细菌、抗真菌、病毒等微生物感染以及杀伤恶性肿瘤细胞等多种生物学功能,具有发展为新型抗菌、抗癌药物的重要应用前景。然而,抗菌肽的溶血毒性仍然是阻碍抗菌肽应用的关键因素。该文主要从螺旋度、两亲性、疏水性、电荷等阳离子抗菌肽自身的结构参数以及膜脂、膜蛋白、糖分子等红细胞膜的结构组分两方面对抗菌肽溶血机制的研究进展进行了综述,并简述了降低溶血性的研究进展,期望能有助于设计治疗潜力的抗菌肽应用于临床。
Cationic antibacterial peptides,which were small molecule polypeptides,have been shown to have antibacterial,antifungal,antivirus and anticancer activities. Therefore,they have gained much attention as potential antimicrobial and anticancer agents in the future. However,the hemolysis is a problem which has hampered its application. The current research progress is about mechanism of hemolysis from two aspects:the structural parameters of antimicrobial peptides,including helicity,amphipathicity,hydrophobicity and net charge; and the composition of erythrocyte membrane,including the membrane lipids,membrane proteins and carbohydrates,are mainly summarized. The progress of reducing the hemolysis is also discussed,expecting to guide the design of therapeutic potential of antimicrobial peptides used in clinical.
引文
[1]Coetzee J,Corcoran C,Prentice E,et al.Emergence of plasmidmediated colistin resistance(MCR-1)among Escherichia coli isolated from South African patients[J].S Afr Med J,2016,106(5):449-450.
[2]Huang Y,Feng Q,Yan Q,et al.Alpha-helical cationic anticancer peptides:a promising candidate of novel anticancer drugs[J].Mini Rev Med Chem,2015,15(1):73-81.
[3]Dennison SR,Phoenix DA.Influence of C-terminal amidation on the efficacy of modelin-5[J].Biochemistry,2011,50(9):1514-1523.
[4]Yan H,Li S,Sun X,et al.Individual substitution analogs of Mel(12-26),melittin's C-terminal 15-residue peptide:their antimicrobial and hemolytic actions[J].FEBS Lett,2003,554(1-2):100-104.
[5]Chen Y,Mant CT,Farmer SW,et al.Rational design of alpha-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index[J].J Biol Chem,2005,280(13):12316-12329.
[6]Huang Y,He L,Li G,et al.Role of helicity ofα-helical antimicrobial peptides to improve specificity[J].Protein Cell,2014,5(8):631-642.
[7]Hollmann A,Martínez M,Noguera ME,et al.Role of amphipathicity and hydrophobicity in the balance between hemolysis and peptide-membrane interactions of three related antimicrobial peptides[J].Colloids Surf B Biointerfaces,2016,141(5):528-536.
[8]Jin L,Bai X,Luan N,et al.A designed tryptophan-and lysine/arginine-rich antimicrobial peptide with therapeutic potential for clinical antibiotic-resistant Candida albicans Vaginitis[J].J Med Chem,2016,59(5):1791-1799.
[9]Huang YB,Wang XF,Wang HY,et al.Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework[J].Mol Cancer Ther,2011,10(3):416-426.
[10]Dathe M,Nikolenko H,Meyer J,et al.Optimization of the antimicrobial activity of magainin peptides by modification of charge[J].FEBS Lett,2001,501(2-3):146-150.
[11]Jiang Z,Vasil AI,Hale JD,et al.Effects of net charge and the number of positively charged residues on biological activity of amphipathicα-helical cationic antimicrobial peptides[J].Biopolymers,2008,90(3):369-383.
[12]Harris F,Dennison SR,Singh J,et al.On the selectivity and efficacy of defense peptides with respect to cancer cells[J].Med Res Rev,2013,33(1):190-234.
[13]Lee JK,Gopal R,Park SC,et al.A proline-hinge alters the characteristics of the amphipathicα-helical AMPs[J].PLo S One,2013,8(7):e67597.
[14]Ghosh S,Bandyopadhyay S,Bhattacharya DK,et al.Altered erythrocyte membrane characteristics during anemia in childhood acute lymphoblastic leukemia[J].Ann Hematol,2005,84(2):76-84.
[15]Li Q,Dong C,Deng A,et al.Hemolysis of erythrocytes by granulysin-derived peptides but not by granulysin[J].Antimicrob Agents Chemother,2005,49(1):388-397.
[16]Dempsey CE,Hawrani A,Howe RA,et al.Amphipathic antimicrobial peptides--from biophysics to therapeutics[J].Protein Pept Lett,2010,17(11):1334-1344.
[17]Dennison SR,Phoenix DA.Susceptibility of sheep,human,and pig erythrocytes to haemolysis by the antimicrobial peptide Modelin 5[J].Eur Biophys J,2014,43(8-9):423-432.
[18]Maher S,Mc Clean S.Melittin exhibits necrotic cytotoxicity in gastrointestinal cells which is attenuated by cholesterol[J].Biochem Pharmacol,2008,75(5):1104-1114.
[19]Raghuraman H,Chattopadhyay A.Cholesterol inhibits the lytic activity of melittin in erythrocytes[J].Chem Phys Lipids,2005,134(2):183-189.
[20]Dennison SR,Phoenix DA.Effect of cholesterol on the membrane interaction of Modelin-5 isoforms[J].Biochem,2011,50(50):10898-10909.
[21]Kumar A,Ali M,Pandey BN,et al.Role of membrane sialic acid and glycophorin protein in thorium induced aggregation and hemolysis of human erythrocytes[J].Biochim,2010,92(7):869-879.
[22]Harris F,Dennison SR,Singh J,et al.On the selectivity and efficacy of defense peptides with respect to cancer cells[J].Med Res Rev,2013,33(1):190-234.
[23]石伟,李彩云,陈玉清.蜂毒肽Melittin对小鼠红细胞溶血效应及影响机制分析[J].南京师大学报(自然科学版),2015,38(2):86-92.
[24]Panteleev PV,Ovchinnikova TV.Improved strategy for recombinant production and purification of antimicrobial peptide tachyplesin I and its analogs with high cell selectivity[J].Biotechnol Appl Biochem,2015,10.1002.1456
[25]Saravanan R,Bhunia A,Bhattacharjya S.Micelle-bound structures and dynamics of the hinge deleted analog of melittin and its diastereomer:implications in cell selective lysis by D-amino acid containing antimicrobial peptides[J].Biochim Biophys Acta,2010,1798(2):128-139.
[26]Jacob B,Rajasekaran G,Kim EY,et al.The stereochemical effect of SMAP-29 and SMAP-18 on bacterial selectivity,membrane interaction and anti-inflammatory activity[J].Amino Acids,2016,48(5):1241-1251.
[27]Jacob B,Kim Y,Hyun JK,et al.Bacterial killing mechanism of sheep myeloid antimicrobial peptide-18(SMAP-18)and its Trpsubstituted analog with improved cell selectivity and reduced mammalian cell toxicity[J].Amino Acids,2014,46(1):187-198.
[28]Gautam A,Chaudhary K,Singh S,et al.Hemolytik:a database of experimentally determined hemolytic and non-hemolytic peptides[J].Nucleic Acids Res,2014,42:D444-D449.
[29]Sahariah P,Srensen KK,Hjálmarsdóttir Má,et al.Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers[J].Chem Commun(Camb),2015,51(58):11611-11614.
[30]Perekalin DS,Novikov VV,Pavlov AA,et al.Selective ruthenium labeling of the tryptophan residue in the bee venom peptide melittin[J].Chemistry,2015,21(13):4923-4925.
