Table Info

Table 3.

Modified residues or molecules to be used in synthesis for special requirements

Amino acid	Use	References
Fmoc-Lys(Fmoc)-OH	Synthesis of peptide dimers using the side chain to grow a new peptide chain	[78]
Fmoc-Lys(Dde)-OH	Used when it is necessary to make bonds with the lysine side chain, for example in the case of branched peptides, template structured peptides, or for bonding with metal groups.
J ligand Malonic or Propanodioic acid	Used to induce structured peptides in conjunction with Lys(Dde)
Fmoc-DOPA-OH	Catecholic amino acid related to adhesive properties of mussel foot proteins	[70]
Deuterated Fmoc-Lys(Boc)-OH	Track of peptide by nuclear magnetic resonance (NMR)	[79]

Compounds structures were drawn with ACD/Chemsketch 2021.2.1 [77]. Fmoc: fluorenylmethyloxycarbonyl; Dde: [1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]; DOPA: L-3,4-dihydroxyphenylalanine; Boc: tert-butoxycarbonyl

Declarations

Acknowledgments

The authors thank all the students who were part of this journey and who have supported each of the reported publications.

Author contributions

CC: Conceptualization, Data Curation, Writing—original draft, Writing—review & editing, Validation, Visualization, Funding acquisition. PS: Writing—review & editing. CA: Data curation, Writing—original draft, Writing—review & editing, Validation. LM and SM: Writing—review & editing. FA: Writing—review & editing, Validation. FG: Conceptualization, Data curation, Validation, Project administration.

Conflicts of interest

Fernando Albericio, the Editor-in-Chief and a Guest Editor of Exploration of Drug Science, and Fanny Guzmán, a Guest Editor of Exploration of Drug Science, had no involvement in the decision-making or the review process of this manuscript. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

FG received financial support from ANID Fondecyt [1210056]. CC received funding support form ANID Fondecyt [1240448]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Canesi L, Auguste M, Balbi T, Prochazkova P. Soluble mediators of innate immunity in annelids and bivalve mollusks: A mini-review. Front Immunol. 2022;13:1051155. [DOI] [PubMed] [PMC]

Feng M, Fei S, Xia J, Labropoulou V, Swevers L, Sun J. Antimicrobial Peptides as Potential Antiviral Factors in Insect Antiviral Immune Response. Front Immunol. 2020;11:2030. [DOI] [PubMed] [PMC]

Hancock RE, Haney EF, Gill EE. The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol. 2016;16:321–34. [DOI] [PubMed]

Lluka T, Stokes JM. Antibiotic discovery in the artificial intelligence era. Ann N Y Acad Sci. 2023;1519:74–93. [DOI] [PubMed]

Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20:309–25. [DOI] [PubMed]

Browne K, Chakraborty S, Chen R, Willcox MD, Black DS, Walsh WR, et al. A New Era of Antibiotics: The Clinical Potential of Antimicrobial Peptides. Int J Mol Sci. 2020;21:7047. [DOI] [PubMed] [PMC]

Zhu Y, Hao W, Wang X, Ouyang J, Deng X, Yu H, et al. Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug-resistant infections. Med Res Rev. 2022;42:1377–422. [DOI] [PubMed]

Jochumsen N, Marvig RL, Damkiær S, Jensen RL, Paulander W, Molin S, et al. The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is shaped by strong epistatic interactions. Nat Commun. 2016;7:13002. [DOI] [PubMed] [PMC]

Kintses B, Jangir PK, Fekete G, Számel M, Méhi O, Spohn R, et al. Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action. Nat Commun. 2019;10:5731. [DOI] [PubMed] [PMC]

10.

Spohn R, Daruka L, Lázár V, Martins A, Vidovics F, Grézal G, et al. Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance. Nat Commun. 2019;10:4538. [DOI] [PubMed] [PMC]

11.

Maron B, Rolff J, Friedman J, Hayouka Z. Antimicrobial Peptide Combination Can Hinder Resistance Evolution. Microbiol Spectr. 2022;10:e0097322. [DOI] [PubMed] [PMC]

12.

Zaky AA, Simal-Gandara J, Eun JB, Shim JH, Abd El-Aty AM. Bioactivities, Applications, Safety, and Health Benefits of Bioactive Peptides From Food and By-Products: A Review. Front Nutr. 2022;8:815640. [DOI] [PubMed] [PMC]

13.

Ashaolu TJ. Antioxidative peptides derived from plants for human nutrition: their production, mechanisms and applications. Eur Food Res Technol. 2020;246:853–65. [DOI]

14.

Karami Z, Akbari-Adergani B. Bioactive food derived peptides: a review on correlation between structure of bioactive peptides and their functional properties. J Food Sci Technol. 2019;56:535–47. [DOI] [PubMed] [PMC]

15.

León Madrazo A, Segura Campos MR. Review of antimicrobial peptides as promoters of food safety: Limitations and possibilities within the food industry. J Food Saf. 2020;40:e12854. [DOI]

16.

Sarabandi K, Gharehbeglou P, Jafari SM. Spray-drying encapsulation of protein hydrolysates and bioactive peptides: Opportunities and challenges. Dry Technol. 2020;38:577–95. [DOI]

17.

Resende DISP, Ferreira MS, Sousa-Lobo JM, Sousa E, Almeida IF. Usage of Synthetic Peptides in Cosmetics for Sensitive Skin. Pharmaceuticals (Basel). 2021;14:702. [DOI] [PubMed] [PMC]

18.

Errante F, Ledwoń P, Latajka R, Rovero P, Papini AM. Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy. Front Chem. 2020;8:572923. [DOI] [PubMed] [PMC]

19.

Zhao X, Zhang X, Liu D. Collagen peptides and the related synthetic peptides: A review on improving skin health. J Funct Foods. 2021;86:104680. [DOI]

20.

Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7:48. [DOI] [PubMed] [PMC]

21.

Al Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2023 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2024;17:243. [DOI] [PubMed] [PMC]

22.

Rossino G, Marchese E, Galli G, Verde F, Finizio M, Serra M, et al. Peptides as Therapeutic Agents: Challenges and Opportunities in the Green Transition Era. Molecules. 2023;28:7165. [DOI] [PubMed] [PMC]

23.

Guzmán F, Gauna A, Roman T, Luna O, Álvarez C, Pareja-Barrueto C, et al. Tea Bags for Fmoc Solid-Phase Peptide Synthesis: An Example of Circular Economy. Molecules. 2021;26:5035. [DOI] [PubMed] [PMC]

24.

Ferrazzano L, Catani M, Cavazzini A, Martelli G, Corbisiero D, Cantelmi P, et al. Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges. Green Chem. 2022;24:975–1020. [DOI]

25.

Groß A, Hashimoto C, Sticht H, Eichler J. Synthetic Peptides as Protein Mimics. Front Bioeng Biotechnol. 2016;3:211. [DOI] [PubMed] [PMC]

26.

Shwaiki LN, Lynch KM, Arendt EK. Future of antimicrobial peptides derived from plants in food application–A focus on synthetic peptides. Trends Food Sci Technol. 2021;112:312–24. [DOI]

27.

Akbarian M, Khani A, Eghbalpour S, Uversky VN. Bioactive Peptides: Synthesis, Sources, Applications, and Proposed Mechanisms of Action. Int J Mol Sci. 2022;23:1445. [DOI] [PubMed] [PMC]

28.

Avci FG, Akbulut BS, Ozkirimli E. Membrane Active Peptides and Their Biophysical Characterization. Biomolecules. 2018;8:77. [DOI] [PubMed] [PMC]

29.

Apostolopoulos V, Bojarska J, Chai TT, Elnagdy S, Kaczmarek K, Matsoukas J, et al. A Global Review on Short Peptides: Frontiers and Perspectives. Molecules. 2021;26:430. [DOI] [PubMed] [PMC]

30.

Ding X, Zhao H, Li Y, Lee AL, Li Z, Fu M, et al. Synthetic peptide hydrogels as 3D scaffolds for tissue engineering. Adv Drug Deliv Rev. 2020;160:78–104. [DOI] [PubMed]

31.

Bethke J, Rojas V, Berendsen J, Cárdenas C, Guzmán F, Gallardo JA, et al. Development of a new antibody for detecting natural killer enhancing factor (NKEF)-like protein in infected salmonids. J Fish Dis. 2012;35:379–88. [DOI] [PubMed]

32.

Álvarez CA, Santana PA, Guzmán F, Marshall S, Mercado L. Detection of the hepcidin prepropeptide and mature peptide in liver of rainbow trout. Dev Comp Immunol. 2013;41:77–81. [DOI] [PubMed]

33.

Chico V, Salvador-Mira ME, Nombela I, Puente-Marin S, Ciordia S, Mena MC, et al. IFIT5 Participates in the Antiviral Mechanisms of Rainbow Trout Red Blood Cells. Front Immunol. 2019;10:613. [DOI] [PubMed] [PMC]

34.

Valero Y, Arizcun M, Cortés J, Ramírez-Cepeda F, Guzmán F, Mercado L, et al. NK-lysin, dicentracin and hepcidin antimicrobial peptides in European sea bass. Ontogenetic development and modulation in juveniles by nodavirus. Dev Comp Immunol. 2020;103:103516. [DOI] [PubMed]

35.

Sáenz-Martínez DE, Santana PA, Aróstica M, Forero JC, Guzmán F, Mercado L. Immunodetection of rainbow trout IL-8 cleaved-peptide: Tissue bioavailability and potential antibacterial activity in a bacterial infection context. Dev Comp Immunol. 2021;124:104182. [DOI] [PubMed]

36.

Morales-Lange B, Ramírez-Cepeda F, Schmitt P, Guzmán F, Lagos L, Øverland M, et al. Interferon Gamma Induces the Increase of Cell-Surface Markers (CD80/86, CD83 and MHC-II) in Splenocytes From Atlantic Salmon. Front Immunol. 2021;12:666356. [DOI] [PubMed] [PMC]

37.

Rice P, Longden I, Bleasby A. EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet. 2000;16:276–7. [DOI] [PubMed]

38.

Jespersen MC, Peters B, Nielsen M, Marcatili P. BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res. 2017;45:W24–9. [DOI] [PubMed] [PMC]

39.

Yao B, Zhang L, Liang S, Zhang C. SVMTriP: a method to predict antigenic epitopes using support vector machine to integrate tri-peptide similarity and propensity. PLoS One. 2012;7:e45152. [DOI] [PubMed] [PMC]

40.

Soria-Guerra RE, Nieto-Gomez R, Govea-Alonso DO, Rosales-Mendoza S. An overview of bioinformatics tools for epitope prediction: implications on vaccine development. J Biomed Inform. 2015;53:405–14. [DOI] [PubMed]

41.

Yang J, Zhang Y. I-TASSER server: new development for protein structure and function predictions. Nucleic Acids Res. 2015;43:W174–81. [DOI] [PubMed] [PMC]

42.

Xu J, Mcpartlon M, Li J. Improved protein structure prediction by deep learning irrespective of co-evolution information. Nat Mach Intell. 2021;3:601–9. [DOI] [PubMed] [PMC]

43.

Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–58. [DOI] [PubMed] [PMC]

44.

Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–303. [DOI] [PubMed] [PMC]

45.

Guzmán F, Aróstica M, Román T, Beltrán D, Gauna A, Albericio F, et al. Peptides, solid-phase synthesis and characterization: Tailor-made methodologies. Electron J Biotechnol. 2023;64:27–33. [DOI]

46.

Prieto I, Hervás-Stubbs S, García-Granero M, Berasain C, Riezu-Boj JI, Lasarte JJ, et al. Simple strategy to induce antibodies of distinct specificity: application to the mapping of gp120 and inhibition of HIV-1 infectivity. Eur J Immunol. 1995;25:877–83. [DOI] [PubMed]

47.

Schmitt P, Wacyk J, Morales-Lange B, Rojas V, Guzmán F, Dixon B, et al. Immunomodulatory effect of cathelicidins in response to a β-glucan in intestinal epithelial cells from rainbow trout. Dev Comp Immunol. 2015;51:160–9. [DOI] [PubMed]

48.

Álvarez CA, Santana PA, Salinas-Parra N, Beltrán D, Guzmán F, Vega B, et al. Immune Modulation Ability of Hepcidin from Teleost Fish. Animals (Basel). 2022;12:1586. [DOI] [PubMed] [PMC]

49.

González R, González D, Stambuk F, Ramírez F, Guzmán F, Mercado L, et al. A g-type lysozyme from the scallop Argopecten purpuratus participates in the immune response and in the stability of the hemolymph microbiota. Fish Shellfish Immunol. 2022;123:324–34. [DOI] [PubMed]

50.

Guzmán F, Marshall S, Ojeda C, Albericio F, Carvajal-Rondanelli P. Inhibitory effect of short cationic homopeptides against gram-positive bacteria. J Pept Sci. 2013;19:792–800. [DOI] [PubMed]

51.

Carvajal-Rondanelli P, Aróstica M, Marshall SH, Albericio F, Álvarez CA, Ojeda C, et al. Inhibitory effect of short cationic homopeptides against Gram-negative bacteria. Amino Acids. 2016;48:1445–56. [DOI] [PubMed]

52.

Carvajal-Rondanelli P, Aróstica M, Álvarez CA, Ojeda C, Albericio F, Aguilar LF, et al. Understanding the antimicrobial properties/activity of an 11-residue Lys homopeptide by alanine and proline scan. Amino Acids. 2018;50:557–68. [DOI] [PubMed]

53.

Aróstica M, Rojas R, Aguilar LF, Carvajal-Rondanelli P, Albericio F, Guzmán F, et al. Arginine Homopeptide of 11 Residues as a Model of Cell-Penetrating Peptides in the Interaction with Bacterial Membranes. Membranes (Basel). 2022;12:1180. [DOI] [PubMed] [PMC]

54.

Rojas R, Aróstica M, Carvajal-Rondanelli P, Albericio F, Guzmán F, Cárdenas C. Relationship between type II polyproline helix secondary structure and thermal hysteresis activity of short homopeptides. Electron J Biotechnol. 2022;59:62–73. [DOI]

55.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera—A visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12. [DOI] [PubMed]

56.

Arenas G, Guzmán F, Cárdenas C, Mercado L, Marshall SH. A novel antifungal peptide designed from the primary structure of a natural antimicrobial peptide purified from Argopecten purpuratus hemocytes. Peptides. 2009;30:1405–11. [DOI] [PubMed]

57.

Alvarez CA, Guzmán F, Cárdenas C, Marshall SH, Mercado L. Antimicrobial activity of trout hepcidin. Fish Shellfish Immunol. 2014;41:93–101. [DOI] [PubMed]

58.

Santana PA, Salinas N, Álvarez CA, Mercado LA, Guzmán F. Alpha-helical domain from IL-8 of salmonids: Mechanism of action and identification of a novel antimicrobial function. Biochem Biophys Res Commun. 2018;498:803–9. [DOI] [PubMed]

59.

Álvarez CA, Santana PA, Luna O, Cárdenas C, Albericio F, Romero MS, et al. Chemical Synthesis and Functional Analysis of VarvA Cyclotide. Molecules. 2018;23:952. [DOI] [PubMed] [PMC]

60.

Álvarez CA, Barriga A, Albericio F, Romero MS, Guzmán F. Identification of Peptides in Flowers of Sambucus nigra with Antimicrobial Activity against Aquaculture Pathogens. Molecules. 2018;23:1033. [DOI] [PubMed] [PMC]

61.

Medina L, Guzmán F, Álvarez C, Delgado JP, Carbonell-M B. Ramosin: The First Antibacterial Peptide Identified on Bolitoglossa ramosi Colombian Salamander. Pharmaceutics. 2022;14:2579. [DOI] [PubMed] [PMC]

62.

Santana PA, Arancibia C, Tamayo L, Cumillaf JP, Roman T, Cárdenas C, et al. First Insights about Antiparasitic and Action Mechanisms of the Antimicrobial Peptide Hepcidin from Salmonids against Caligus rogercresseyi. Pharmaceutics. 2024;16:378. [DOI] [PubMed] [PMC]

63.

Intiquilla A, Jiménez-Aliaga K, Guzmán F, Alvarez CA, Zavaleta AI, Izaguirre V, et al. Novel antioxidant peptides obtained by alcalase hydrolysis of Erythrina edulis (pajuro) protein. J Sci Food Agric. 2019;99:2420–7. [DOI] [PubMed]

64.

Guzmán F, Wong G, Román T, Cárdenas C, Alvárez C, Schmitt P, et al. Identification of Antimicrobial Peptides from the Microalgae Tetraselmis suecica (Kylin) Butcher and Bactericidal Activity Improvement. Mar Drugs. 2019;17:453. [DOI] [PubMed] [PMC]

65.

León R, Ruiz M, Valero Y, Cárdenas C, Guzman F, Vila M, et al. Exploring small cationic peptides of different origin as potential antimicrobial agents in aquaculture. Fish Shellfish Immunol. 2020;98:720–7. [DOI] [PubMed]

66.

Valero Y, González-Fernández C, Cárdenas C, Guzmán F, León R, Cuesta A. NK-lysin peptides ameliorate viral encephalopathy and retinopathy disease signs and provide partial protection against nodavirus infection in European sea bass. Antiviral Res. 2021;192:105104. [DOI] [PubMed]

67.

Cárdenas C, Guzmán F, Carmona M, Muñoz C, Nilo L, Labra A, et al. Synthetic Peptides as a Promising Alternative to Control Viral Infections in Atlantic Salmon. Pathogens. 2020;9:600. [DOI] [PubMed] [PMC]

68.

Nuñez SM, Guzmán F, Valencia P, Almonacid S, Cárdenas C. Collagen as a source of bioactive peptides: A bioinformatics approach. Electron J Biotechnol. 2020;48:101–8. [DOI]

69.

Bartsch IM, Perelmuter K, Bollati-Fogolín M, Bartsch JA, Guzmán F, Marshall SH. An in vitro model mimicking the complement system to favor directed phagocytosis of unwanted cells. Electron J Biotechnol. 2021;49:5–13. [DOI]

70.

Gauna A, Mercado L, Guzmán F. Antimicrobial characterization of a titanium coating derived from mussel-glue and Bothrops asper snake venom for the prevention of implant-associated infections caused by Staphylococcus. Electron J Biotechnol. 2022;56:31–8. [DOI]

71.

Morrison KL, Weiss GA. Combinatorial alanine-scanning. Curr Opin Chem Biol. 2001;5:302–7. [DOI] [PubMed]

72.

Migoń D, Jaśkiewicz M, Neubauer D, Bauer M, Sikorska E, Kamysz E, et al. Alanine Scanning Studies of the Antimicrobial Peptide Aurein 1.2. Probiotics Antimicrob Proteins. 2019;11:1042–54. [DOI] [PubMed] [PMC]

73.

Grieco P, Luca V, Auriemma L, Carotenuto A, Saviello MR, Campiglia P, et al. Alanine scanning analysis and structure-function relationships of the frog-skin antimicrobial peptide temporin-1Ta. J Pept Sci. 2011;17:358–65. [DOI] [PubMed]

74.

Raguine L, Ali M, Bender V, Diefenbach E, Doddareddy MR, Hibbs D, et al. Alanine scan of an immunosuppressive peptide (CP): analysis of structure-function relationships. Chem Biol Drug Des. 2013;81:167–74. [DOI] [PubMed]

75.

Jofré C, Guzmán F, Cárdenas C, Albericio F, Marshall SH. A natural peptide and its variants derived from the processing of infectious pancreatic necrosis virus (IPNV) displaying enhanced antimicrobial activity: a novel alternative for the control of bacterial diseases. Peptides. 2011;32:852–8. [DOI] [PubMed]

76.

Álvarez CA, Alvarado JF, Farías M, Cárcamo CB, Flores H, Guzmán F, et al. First insights about orexigenic activity and gastrointestinal tissue localization of ghrelin from Corvina drum (Cilus gilberti). Aquaculture. 2023;571:739468. [DOI]

77.

ACD/Chemsketch Version 2021. 2.1 [software]. Advanced Chemistry Development I (ACD/Labs). [cited 2024 Jun 10]. Available from: https://www.acdlabs.com/

78.

Barrera NF, Melgarejo LM, Cruz-Gallego M, Cortés LJ, Guzmán F, Calvo JC. Conformationally Restricted Peptides from Rice Proteins Elicit Antibodies That Recognize the Corresponding Native Protein in ELISA Assays. Molecules. 2018;23:2262. [DOI] [PubMed] [PMC]

79.

Muñoz-Gacitúa D, Guzman F, Weiss-López B. Insights into the equilibrium structure and translocation mechanism of TP1, a spontaneous membrane-translocating peptide. Sci Rep. 2022;12:19880. [DOI] [PubMed] [PMC]

80.

Bucataru C, Ciobanasu C. Antimicrobial peptides: Opportunities and challenges in overcoming resistance. Microbiol Res. 2024;286:127822. [DOI] [PubMed]

81.

Chen N, Jiang C. Antimicrobial peptides: Structure, mechanism, and modification. Eur J Med Chem. 2023;255:115377. [DOI] [PubMed]

82.

Fetse J, Kandel S, Mamani UF, Cheng K. Recent advances in the development of therapeutic peptides. Trends Pharmacol Sci. 2023;44:425–41. [DOI] [PubMed] [PMC]

83.

Pereira AJ, de Campos LJ, Xing H, Conda-Sheridan M. Peptide-based therapeutics: challenges and solutions. Med Chem Res. 2024;33:1275–80. [DOI]

84.

Todaro B, Ottalagana E, Luin S, Santi M. Targeting Peptides: The New Generation of Targeted Drug Delivery Systems. Pharmaceutics. 2023;15:1648. [DOI] [PubMed] [PMC]

85.

Yang S, Wang M, Wang T, Sun M, Huang H, Shi X, et al. Self-assembled short peptides: Recent advances and strategies for potential pharmaceutical applications. Mater Today Bio. 2023;20:100644. [DOI] [PubMed] [PMC]

86.

Shi M, McHugh KJ. Strategies for overcoming protein and peptide instability in biodegradable drug delivery systems. Adv Drug Deliv Rev. 2023;199:114904. [DOI] [PubMed] [PMC]

87.

Wang J, Chen L, Qin S, Xie M, Luo SZ, Li W. Advances in biosynthesis of peptide drugs: Technology and industrialization. Biotechnol J. 2024;19:e2300256. [DOI] [PubMed]