Clinical Application of AMPs

  • Fabíola Costa
  • Cátia Teixeira
  • Paula Gomes
  • M. Cristina L. MartinsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1117)


Antimicrobial peptides (AMPs) have been described as one of the most promising compounds able to address one of the main health threats of the twenty-first century that is the continuous rise of multidrug-resistant microorganisms. However, despite the clear advantages of AMPs as a new class of antimicrobials, such as broad spectrum of activity, high selectivity, low toxicity and low propensity to induce resistance, only a small fraction of AMPs reported thus far have been able to successfully complete all phases of clinical trials and become accessible to patients. This is mainly related to the low bioavailability and still somewhat expensive production of AMP along with regulatory obstacles. This chapter offers an overview of selected AMPs that are currently in the market or under clinical trials. Strategies for assisting AMP industrial translation and major regulatory difficulties associated with AMP approval for clinical evaluation will be also discussed.


  1. Afacan NJ, Yeung AT, Pena OM, Hancock RE (2012) Therapeutic potential of host defense peptides in antibiotic-resistant infections. Curr Pharm Des 18(6):807–819PubMedGoogle Scholar
  2. Ahn HS, Cho W, Kim JM, Joshi BP, Park JW, Lohani CR, Cho H, Lee KH (2008) Design and synthesis of cyclic disulfide-bonded antibacterial peptides on the basis of the alpha helical domain of Tenecin 1, an insect defensin. Bioorg Med Chem 16(7):4127–4137PubMedGoogle Scholar
  3. Almaaytah A, Mohammed GK, Abualhaijaa A, Al-Balas Q (2017) Development of novel ultrashort antimicrobial peptide nanoparticles with potent antimicrobial and antibiofilm activities against multidrug-resistant bacteria. Drug Des Dev Ther 11:3159–3170Google Scholar
  4. Alminana N, Alsina MA, Ortiz A, Reig F (2004) Comparative physicochemical study of SIKVAV peptide and its retro and retro-enantio analogues. Colloids Surf A: Physicochem Eng Asp 249(1–3):19–24Google Scholar
  5. Arias M, Piga KB, Hyndman ME, Vogel HJ (2018) Improving the activity of Trp-rich antimicrobial peptides by Arg/Lys substitutions and changing the length of cationic residues. Biomolecules 8(2):1–17Google Scholar
  6. Bednarska NG, Wren BW, Willcocks SJ (2017) The importance of the glycosylation of antimicrobial peptides: natural and synthetic approaches. Drug Discov Today 22(6):919–926PubMedGoogle Scholar
  7. Blin T, Purohit V, Leprince J, Jouenne T, Glinel K (2011) Bactericidal microparticles decorated by an antimicrobial peptide for the easy disinfection of sensitive aqueous solutions. Biomacromolecules 12(4):1259–1264PubMedGoogle Scholar
  8. Bourne DG, Jones GJ, Blakeley RL, Jones A, Negri AP, Riddles P (1996) Enzymatic pathway for the bacterial degradation of the cyanobacterial cyclic peptide toxin microcystin LR. Appl Environ Microbiol 62(11):4086–4094PubMedPubMedCentralGoogle Scholar
  9. Brooks BD, Brooks AE (2014) Therapeutic strategies to combat antibiotic resistance. Adv Drug Deliv Rev 78:14–27PubMedGoogle Scholar
  10. Cardoso MH, Cândido ES, Oshiro KGN, Rezende SB, Franco OL (2018) Peptides containing D-amino acids and retro-inverso peptides: general applications and special focus on antimicrobial peptides. In: Koutsopoulos S (ed) Peptide applications in biomedicine, biotechnology and bioengineering. Woodhead Publishing, Elsevier Ltd, Kidlington, pp 131–155Google Scholar
  11. Carmona-Ribeiro AM, Carrasco LDD (2014) Novel formulations for antimicrobial peptides. Int J Mol Sci 15(10):18040–18083PubMedPubMedCentralGoogle Scholar
  12. Chatterjee J, Rechenmacher F, Kessler H (2013) N-methylation of peptides and proteins: an important element for modulating biological functions. Angew Chem Int Ed 52(1):254–269Google Scholar
  13. Cheneval O, Schroeder CI, Durek T, Walsh P, Huang YH, Liras S, Price DA, Craik DJ (2014) Fmoc-based synthesis of disulfide-rich cyclic peptides. J Org Chem 79(12):5538–5544PubMedGoogle Scholar
  14. Chicharro C, Granata C, Lozano R, Andreu D, Rivas L (2001) N-terminal fatty acid substitution increases the leishmanicidal activity of CA(1-7)M(2-9), a cecropin-melittin hybrid peptide. Antimicrob Agents Chemother 45(9):2441–2449PubMedPubMedCentralGoogle Scholar
  15. Chu Q, Moellering RE, Hilinski GJ, Kim YW, Grossmann TN, Yeh JTH, Verdine GL (2015) Towards understanding cell penetration by stapled peptides. Medchemcomm 6(1):111–119Google Scholar
  16. (n.d.)
  17. ClinicalTrialsPage (n.d.) Accessed Jul 2018.
  18. Coates ARM, Halls G, Hu YM (2011) Novel classes of antibiotics or more of the same? Br J Pharmacol 163(1):184–194PubMedPubMedCentralGoogle Scholar
  19. Cochrane SA, Findlay B, Bakhtiary A, Acedo JZ, Rodriguez-Lopez EM, Mercier P, Vederas JC (2016) Antimicrobial lipopeptide tridecaptin A(1) selectively binds to gram-negative lipid II. Proc Natl Acad Sci U S A 113(41):11561–11566PubMedPubMedCentralGoogle Scholar
  20. Collins JJ, Koeris M, Lu TKT, et al. (2015) Bacteriophages expressing antimicrobial peptides and uses thereof. US 2015/0050717 A1Google Scholar
  21. Costa F, Carvalho IF, Montelaro RC, Gomes P, Martins MCL (2011) Covalent immobilization of antimicrobial peptides (AMPs) onto biomaterial surfaces. Acta Biomater 7(4):1431–1440PubMedGoogle Scholar
  22. Costa FMTA, Maia SR, Gomes PAC, Martins MCL (2015) Dhvar5 antimicrobial peptide (AMP) chemoselective covalent immobilization results on higher antiadherence effect than simple physical adsorption. Biomaterials 52:531–538PubMedGoogle Scholar
  23. d’Angelo I, Casciaro B, Miro A, Quaglia F, Mangoni ML, Ungaro F (2015) Overcoming barriers in Pseudomonas aeruginosa lung infections: engineered nanoparticles for local delivery of a cationic antimicrobial peptide. Colloids Surf B:Biointerfaces 135:717–725PubMedGoogle Scholar
  24. Davies JS (2003) The cyclization of peptides and depsipeptides. J Pept Sci 9(8):471–501PubMedGoogle Scholar
  25. Di L (2015) Strategic approaches to optimizing peptide ADME properties. AAPS J 17(1):134–143PubMedGoogle Scholar
  26. Di Pisa M, Chassaing G, Swiecicki JM (2015) When cationic cell-penetrating peptides meet hydrocarbons to enhance in-cell cargo delivery. J Pept Sci 21(5):356–369PubMedGoogle Scholar
  27. Doak BC, Over B, Giordanetto F, Kihlberg J (2014) Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem Biol 21(9):1115–1142PubMedGoogle Scholar
  28. Doherty DH, Rosendahl MS, Smith DJ, Hughes JM, Chlipala EA, Cox GN (2005) Site-specific PEGylation of engineered cysteine analogues of recombinant human granulocyte-macrophage colony-stimulating factor. Bioconjug Chem 16(5):1291–1298PubMedPubMedCentralGoogle Scholar
  29. Doores KJ, Gamblin DP, Davis BG (2006) Exploring and exploiting the therapeutic potential of glycoconjugates. Chem Eur J 12(3):656–665PubMedGoogle Scholar
  30. DrugDataBase (n.d.) Accessed Jul 2018.
  31. Eckert RH, Yarbrough D, Shi W, et al (2014) Selectively targeted antimicrobial peptides and the use thereof. EP2801368A1 2014Google Scholar
  32. Falanga A, Lombardi L, Franci G, Vitiello M, Iovene MR, Morelli G, Galdiero M, Galdiero S (2016) Marine antimicrobial peptides: nature provides templates for the design of novel compounds against pathogenic bacteria. Int J Mol Sci 17(5):1–17Google Scholar
  33. Falanga A, Nigro E, De Biasi MG, Daniele A, Morelli G, Galdiero S, Scudiero O (2017) Cyclic peptides as novel therapeutic microbicides: engineering of human defensin mimetics. Molecules 22(7):1–15Google Scholar
  34. Fang Y, Xue JX, Gao S, Lu AQ, Yang DJ, Jiang H, He Y, Shi K (2017) Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery. Drug Deliv 24(2):22–32PubMedGoogle Scholar
  35. Fernandes P, Martens E (2017) Antibiotics in late clinical development. Biochem Pharmacol 133:152–163PubMedGoogle Scholar
  36. Fishburn CS (2008) The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 97(10):4167–4183PubMedGoogle Scholar
  37. Fox JL (2013) Antimicrobial peptides stage a comeback(vol 31, pg 379, 2013). Nat Biotechnol 31(12):1066–1066Google Scholar
  38. Giuliani A, Pirri G, Nicoletto SF (2007) Antimicrobial peptides: an overview of a promising class of therapeutics. Cent Eur J Biol 2(1):1–33Google Scholar
  39. Gomes A, Teixeira C, Ferraz R, Prudencio C, Gomes P (2017) Wound-healing peptides for treatment of chronic diabetic foot ulcers and other infected skin injuries. Molecules 22(10):2–18Google Scholar
  40. Gong Y, Andina D, Nahar S, Leroux JC, Gauthier MA (2017) Releasable and traceless PEGylation of arginine-rich antimicrobial peptides. Chem Sci 8(5):4082–4086PubMedPubMedCentralGoogle Scholar
  41. Gordon YJ, Romanowski EG, McDermott AM (2005) A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr Eye Res 30(7):505–515PubMedPubMedCentralGoogle Scholar
  42. Greber KE, Dawgul M (2017) Antimicrobial peptides under clinical trials. Curr Top Med Chem 17(5):620–628PubMedGoogle Scholar
  43. Guiotto A, Pozzobon M, Canevari M, Manganelli R, Scarin M, Veronese FM (2003) PEGylation of the antimicrobial peptide nisin a: problems and perspectives. Farmaco 58(1):45–50PubMedGoogle Scholar
  44. Hamley IW (2014) PEG-peptide conjugates. Biomacromolecules 15(5):1543–1559PubMedGoogle Scholar
  45. Hancock RE, Sahl HG (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24(12):1551–1557Google Scholar
  46. Henninot A, Collins JC, Nuss JM (2018) The current state of peptide drug discovery: back to the future? J Med Chem 61(4):1382–1414PubMedGoogle Scholar
  47. Hoffmann R, Berthold N, Nollmann F (2014). Modified antibiotic peptides having variable systemic release. US20140309161 A1. 2014Google Scholar
  48. Imura Y, Nishida M, Ogawa Y, Takakura Y, Matsuzaki K (2007) Action mechanism of tachyplesin I and effects of PEGylation. Biochim Biophys Acta-Biomembr 1768(5):1160–1169Google Scholar
  49. Joo SH (2012) Cyclic peptides as therapeutic agents and biochemical tools. Biomol Ther 20(1):19–26Google Scholar
  50. Kosikowska P, Lesner A (2016) Antimicrobial peptides (AMPs) as drug candidates: a patent review (2003-2015). Expert Opin Ther Pat 26(6):689–702PubMedGoogle Scholar
  51. Lambert JN, Mitchell JP, Roberts KD (2001) The synthesis of cyclic peptides. J Chem Soc-Perkin Trans 1(5):471–484Google Scholar
  52. Lau JL, Dunn MK (2018) Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem 26(10):2700–2707PubMedGoogle Scholar
  53. Lele DS, Talat S, Kumari S, Srivastava N, Kaur KJ (2015) Understanding the importance of glycosylated threonine and stereospecific action of Drosocin, a proline rich antimicrobial peptide. Eur J Med Chem 92:637–647PubMedGoogle Scholar
  54. Lundquist P, Artursson P (2016) Oral absorption of peptides and nanoparticles across the human intestine: opportunities, limitations and studies in human tissues. Adv Drug Deliv Rev 106:256–276PubMedGoogle Scholar
  55. Mahlapuu M, Hakansson J, Ringstad L, Bjorn C (2016) Antimicrobial peptides: an emerging category of therapeutic agents. Front Cell Infect Microbiol 6:1–12Google Scholar
  56. Marti-Centelles V, Pandey MD, Burguete MI, Luis SV (2015) Macrocyclization reactions: the importance of conformational, configurational, and template-induced preorganization. Chem Rev 115(16):8736–8834PubMedGoogle Scholar
  57. Martinez JL (2014) General principles of antibiotic resistance in bacteria. Drug Discov Today Technol 11:33–39PubMedGoogle Scholar
  58. Marx V (2005) Watching peptide drugs grow up. Chem Eng News 83(11):17–84Google Scholar
  59. Melo MN, Castanho MARB (2007) Omiganan interaction with bacterial membranes and cell wall models. Assigning a biological role to saturation. Biochim Biophys Acta-Biomembr 1768(5):1277–1290Google Scholar
  60. Merrifield RB, Juvvadi P, Andreu D, Ubach J, Boman A, Boman HG (1995) Retro and retroenantio analogs of cecropin-melittin hybrids. Proc Natl Acad Sci U S A 92(8):3449–3453PubMedPubMedCentralGoogle Scholar
  61. Migon D, Neubauer D, Kamysz W (2018) Hydrocarbon stapled antimicrobial peptides. Protein J 37(1):2–12PubMedPubMedCentralGoogle Scholar
  62. Molchanova N, Hansen PR, Franzyk H (2017) Advances in development of antimicrobial peptidomimetics as potential drugs. Molecules 22(9):1–60Google Scholar
  63. Monaim SAHA, Jad YE, El-Faham A, de la Torre BG, Albericio F (2018) Teixobactin as a scaffold for unlimited new antimicrobial peptides: SAR study. Bioorg Med Chem 26(10):2788–2796PubMedGoogle Scholar
  64. Moradi SV, Hussein WM, Varamini P, Simerska P, Toth I (2016) Glycosylation, an effective synthetic strategy to improve the bioavailability of therapeutic peptides. Chem Sci 7(4):2492–2500PubMedPubMedCentralGoogle Scholar
  65. Morris CJ, Beck K, Fox MA, Ulaeto D, Clark GC, Gumbleton M (2012) Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery. Antimicrob Agents Chemother 56(6):3298–3308PubMedPubMedCentralGoogle Scholar
  66. Mygind PH, Fischer RL, Schnorr KM, Hansen MT, Sonksen CP, Ludvigsen S, Raventos D, Buskov S, Christensen B, De Maria L, Taboureau O, Yaver D, Elvig-Jorgensen SG, Sorensen MV, Christensen BE, Kjaerulff S, Frimodt-Moller N, Lehrer RI, Zasloff M, Kristensen HH (2005) Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 437(7061):975–980PubMedGoogle Scholar
  67. Oh D, Shirazi AN, Northup K, Sullivan B, Tiwari RK, Bisoffi M, Parang K (2014) Enhanced cellular uptake of short polyarginine peptides through fatty acylation and cyclization. Mol Pharm 11(8):2845–2854PubMedPubMedCentralGoogle Scholar
  68. Otvos L, Wade JD (2014) Current challenges in peptide-based drug discovery. Front Chem 2:1–4Google Scholar
  69. Pfalzgraff A, Brandenburg K, Weindl G (2018) Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front Pharmacol 9:1–23Google Scholar
  70. Qvit N, Rubin SJS, Urban TJ, Mochly-Rosen D, Gross ER (2017) Peptidomimetic therapeutics: scientific approaches and opportunities. Drug Discov Today 22(2):454–462PubMedGoogle Scholar
  71. Rader AFB, Reichart F, Weinmuller M, Kessler H (2018) Improving oral bioavailability of cyclic peptides by N-methylation. Bioorg Med Chem 26(10):2766–2773PubMedGoogle Scholar
  72. Rai A, Pinto S, Evangelista MB, Gil H, Kallip S, Ferreira MGS, Ferreira L (2016a) High-density antimicrobial peptide coating with broad activity and low cytotoxicity against human cells. Acta Biomater 33:64–77PubMedGoogle Scholar
  73. Rai A, Pinto S, Velho TR, Ferreira AF, Moita C, Trivedi U, Evangelista M, Comune M, Rumbaugh KP, Simoes PN, Moita L, Ferreira L (2016b) One-step synthesis of high-density peptide-conjugated gold nanoparticles with antimicrobial efficacy in a systemic infection model. Biomaterials 85:99–110Google Scholar
  74. Rajchakit U, Sarojini V (2017) Recent developments in antimicrobial-peptide-conjugated gold nanoparticles. Bioconjug Chem 28(11):2673–2686PubMedGoogle Scholar
  75. Reinhardt A, Neundorf I (2016) Design and application of antimicrobial peptide conjugates. Int J Mol Sci 17(5):1–21Google Scholar
  76. Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54(4):459–476PubMedGoogle Scholar
  77. Sader HS, Fedler KA, Rennie RP, Stevens S, Jones RN (2004) Omiganan pentahydrochloride (MBI 226), a topical 12-amino-acid cationic peptide: spectrum of antimicrobial activity and measurements of bactericidal activity. Antimicrob Agents Chemother 48(8):3112–3118PubMedPubMedCentralGoogle Scholar
  78. Santajit S, Indrawattana N (2016) Mechanisms of antimicrobial resistance in ESKAPE pathogens. Biomed Res Int 2016(2475067):1–8Google Scholar
  79. Schmidt EGW, Hvam ML, Antunes F, Cameron J, Viuff D, Andersen B, Kristensen NN, Howard KA (2017) Direct demonstration of a neonatal Fc receptor (FcRn)-driven endosomal sorting pathway for cellular recycling of albumin. J Biol Chem 292(32):13312–13322PubMedPubMedCentralGoogle Scholar
  80. Scorciapino MA, Serra I, Manzo G, Rinaldi AC (2017) Antimicrobial dendrimeric peptides: structure, activity and new therapeutic applications. Int J Mol Sci 18(3):1–13Google Scholar
  81. Scott A (2018) Peptide makers face threat from biotechnology how a 1-year-old German start-up could be about to shake up a $1 billion market. Chem Eng News 96(5):4–4Google Scholar
  82. Sierra JM, Fuste E, Rabanal F, Vinuesa T, Vinas M (2017) An overview of antimicrobial peptides and the latest advances in their development. Expert Opin Biol Ther 17(6):663–676PubMedGoogle Scholar
  83. Silva T, Magalhaes B, Maia S, Gomes P, Nazmi K, Bolscher JGM, Rodrigues PN, Bastos M, Gomes MS (2014) Killing of mycobacterium avium by lactoferricin peptides: improved activity of arginine- and D-amino-acid-containing molecules. Antimicrob Agents Chemother 58(6):3461–3467PubMedPubMedCentralGoogle Scholar
  84. Sockolosky JT, Szoka FC (2015) The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Adv Drug Deliv Rev 91:109–124PubMedPubMedCentralGoogle Scholar
  85. Swiecicki JM, Di Pisa M, Lippi F, Chwetzoff S, Mansuy C, Trugnan G, Chassaing G, Lavielle S, Burlina F (2015) Unsaturated acyl chains dramatically enhanced cellular uptake by direct translocation of a minimalist oligo-arginine lipopeptide. Chem Commun 51(78):14656–14659Google Scholar
  86. Tam JP, Lu YA, Yang JL (2002) Antimicrobial dendrimeric peptides. Eur J Biochem 269(3):923–932PubMedGoogle Scholar
  87. Tapeinou A, Matsoukas MT, Simal C, Tselios T (2015) Cyclic peptides on a merry-go-round; towards drug design. Biopolymers 104(5):453–461PubMedGoogle Scholar
  88. Teixeira V, Feio MJ, Rivas L, De la Torre BG, Andreu D, Coutinho A, Bastos M (2010) Influence of lysine N-epsilon-trimethylation and lipid composition on the membrane activity of the cecropin A-melittin hybrid peptide CA(1-7)M(2-9). J Phys Chem B 114(49):16198–16208PubMedGoogle Scholar
  89. Thayer AM (2011) Making peptides at large scale. Chem Eng News 89(22):21–25Google Scholar
  90. Trier S, Linderoth L, Bjerregaard S, Andresen TL, Rahbek UL (2014) Acylation of glucagon-like peptide-2: interaction with lipid membranes and in vitro intestinal permeability. PLoS One 9(10):1–10Google Scholar
  91. Usmani SS, Bedi G, Samuel JS, Singh S, Kalra S, Kumar P, Ahuja AA, Sharma M, Gautam A, Raghava GPS (2017) THPdb: database of FDA-approved peptide and protein therapeutics. PLoS One 12(7):1–12Google Scholar
  92. Veronese FM (2001) Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 22(5):405–417PubMedGoogle Scholar
  93. Vidal L, Geffard M (2014) Lauryl-poly-L-lysine: a new antimicrobial agent? FEBS J 281:328–328Google Scholar
  94. Walensky LD, Bird GH (2014) Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem 57(15):6275–6288PubMedPubMedCentralGoogle Scholar
  95. Wang G, Mishra B, Lau K, Lushnikova T, Golla R, Wang X (2015) Antimicrobial peptides in 2014. Pharmaceuticals (Basel) 8(1):123–150Google Scholar
  96. WebPage, P (n.d.) Accessed Jul 2018.
  97. White CJ, Yudin AK (2011) Contemporary strategies for peptide macrocyclization. Nat Chem 3(7):509–524PubMedGoogle Scholar
  98. Willcox MDP, Kumar N, Cole N, et al. (2013) Antimicrobial peptides and uses thereof. WO2013076666 A1. 2013Google Scholar
  99. Wu YD, Gellman S (2008) Peptidomimetics. Acc Chem Res 41(10):1231–1232PubMedGoogle Scholar
  100. Yang J, Chen H, Vlahov IR, Cheng JX, Low PS (2006) Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging. Proc Natl Acad Sci U S A 103(37):13872–13877PubMedPubMedCentralGoogle Scholar
  101. Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415(6870):389–395Google Scholar
  102. Zong JY, Cobb SL, Cameron NR (2017) Peptide-functionalized gold nanoparticles: versatile biomaterials for diagnostic and therapeutic applications. Biomater Sci 5(5):872–886PubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Fabíola Costa
    • 1
    • 2
  • Cátia Teixeira
    • 3
  • Paula Gomes
    • 3
  • M. Cristina L. Martins
    • 1
    • 2
    • 4
    Email author
  1. 1.i3S, Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  2. 2.INEB, Instituto de Engenharia BiomédicaUniversidade do PortoPortoPortugal
  3. 3.LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de CiênciasUniversidade do PortoPortoPortugal
  4. 4.Instituto de Ciências Biomédicas Abel SalazarUniversidade do PortoPortoPortugal

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