Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Design and synthesis of amphiphilic alternating peptides with lower critical solution temperature behaviors

Polymer Journal volume 54, pages 903–912 (2022)Cite this article

Subjects

Abstract

Amphiphilic peptides consisting of an alternating binary pattern of repeating hydrophilic and hydrophobic units were synthesized via polymerization exploiting Ugi’s four-component condensation reaction (Ugi’s 4CC) as the fundamental polymerization reaction. We performed turbidity measurements of the aqueous polymer solutions at various temperatures. The results showed that the structural effects of the alternating peptides had the following impacts on thermoresponsiveness: (i) amphiphilic alternating peptides with repeating hydrophilic and hydrophobic units tended to adopt upper critical solution temperature (UCST) behavior; and (ii) when the hydrophobes in the polymer were large enough for intrachain hydrophobic interactions, the polymer displayed lower critical solution temperature (LCST) behavior. In addition, we prepared thermoresponsive hydrogels comprising poly(N,N-dimethylacrylamide) as the main chain with alternating peptide skeletons as the cross-linking points. The swellability of the hydrogels in water was clearly dependent on temperature, indicating that the thermal transition of the alternating peptides as the cross-linking points led to the hydrogel volume change. Alternating peptides with LCST behavior may be useful for creating peptide-based smart materials in the future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Scheme 1
Fig. 5

Similar content being viewed by others

References

  1. Danielli F, de Sousa B. The role of plastic concerning the sustainable development goals: the literature point of view. Clean Respons Consum. 2021;3:100020/1–24.

    Google Scholar 

  2. Walker TR. (Micro)plastics and the UN sustainable development goals. Curr Opin Green Sust Chem. 2021;30:100497/1–9.

    Google Scholar 

  3. van Hest JCM. Biosynthetic-synthetic polymer conjugates. J Macromol Sci, Part C: Polym Rev. 2007;47:63–92.

    Google Scholar 

  4. Deming TJ. Polypeptide materials. New synthetic methods and applications. Adv Mater. 1997;9:299–311.

    Article  CAS  Google Scholar 

  5. Deming TJ. Synthesis of side-chain modified polypeptides. Chem Rev. 2016;116:786–808.

    Article  CAS  Google Scholar 

  6. Smith LA, Ma PX. Nano-fibrous scaffolds for tissue engineering. Colloids Surf B. 2004;39:125–31.

    Article  CAS  Google Scholar 

  7. Sell SA, McClure MJ, Garg K, Wolfe PS, Bowlin GL. Electrospinning of collagen/biopolymers for regenerative medicine and cardiovascular tissue engineering. Adv Drug Deliv Rev. 2009;61:1007–19.

    Article  CAS  Google Scholar 

  8. Lee TAT, Cooper A, Apkarian RP, Conticello VP. Thermo-reversible self-assembly of nanoparticles derived from elastin-mimetic polypeptides. Adv Mater. 2000;12:1105–10.

    Article  CAS  Google Scholar 

  9. Chilkoti A, Dreher MR, Meyer DE, Raucher D. Targeted drug delivery by thermally responsive polymers. Adv Drug Deliv Rev. 2002;54:623–30.

    Google Scholar 

  10. Bidwell GL, Fokt I, Priebe W, Raucher D. Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin. Biochem Pharmacol. 2007;73:620–31.

    Article  CAS  Google Scholar 

  11. Trabbic-Carlson K, Setton LA, Chilkoti A. Swelling and mechanical behaviors of chemically cross-linked hydrogels of elastin-like polypeptides. Biomacromolecules. 2003;4:572–80.

    Article  CAS  Google Scholar 

  12. Chin SM, Synatschke CV, Liu S, Nap RJ, Sather NA, Wang Q, et al. Covalent-supramolecular hybrid polymers as muscle-inspired anisotropic actuators. Nat Commun. 2018;9:2395/1–11.

    Google Scholar 

  13. Lim DW, Nettles DL, Setton LA, Chilkoti A. Rapid cross-linking of elastin-like polypeptides with (hydroxymethyl)phosphines in aqueous solution. Biomacromolecules. 2007;8:1463–70.

    Article  CAS  Google Scholar 

  14. Balu R, Dutta NK, Dutta AK, Choudhury NR. Resilin-mimetics as a smart biomaterial platform for biomedical applications. Nat Commun. 2012;12:149/1–15.

    Google Scholar 

  15. Hu R, Li W, Tang BZ. Recent advances in alkyne-based multicomponent polymerizations. Macromol Chem Phys. 2016;217:213–24.

    Article  CAS  Google Scholar 

  16. Zhang Z, You Y, Hong C. Multicomponent reactions and multicomponent cascade reactions for the synthesis of sequence-controlled polymers. Macromol Rapid Commun. 2018;39:1800362/1–12.

    Google Scholar 

  17. Kakuchi R. Multicomponent reactions in polymer synthesis. Angew Chem, Int Ed. 2014;53:46–48.

    Article  CAS  Google Scholar 

  18. Tao Y, Tao Y. Ugi reaction of amino acids: From facile synthesis of polypeptoids to sequence-defined macromolecules. Macromol Rapid Commun. 2021;42:2000515/1–9.

    Article  Google Scholar 

  19. Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angew Chem, Int Ed. 2000;39:3168–210.

    Article  Google Scholar 

  20. Ugi I, Werner B, Dömling A. The chemistry of isocyanides, their multicomponent reactions and their libraries. Molecules. 2003;8:53–66.

    Article  CAS  Google Scholar 

  21. Sharma UK, Sharma N, Vachhani DD, van der Eycken EV. Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds. Chem Soc Rev. 2015;44:1836–60.

    Article  CAS  Google Scholar 

  22. Koyama Y, Gudeangadi PG. One-pot synthesis of alternating peptides exploiting a new polymerization technique based on Ugi’s 4CC reaction. Chem Commun. 2017;53:3846–9.

    Article  CAS  Google Scholar 

  23. Ihsan AB, Koyama Y. Impact of polypeptide sequence on thermal properties for diblock, random, and alternating copolymers containing a stoichiometric mixture of glycine and valine. Polymer. 2019;161:197–204.

    Article  CAS  Google Scholar 

  24. Ihsan AB, Nargis M, Koyama Y. Effects of the hydrophilic-lipophilic balance of alternating peptides on self-assembly and thermo-responsive behaviors. Int J Mol Sci. 2019;20:4604/1–11.

    Article  Google Scholar 

  25. Li W, Chung H, Daeffler C, Johnson JA, Grubbs RH. Application of 1H DOSY for facile measurements of polymer molecular weights. Macromolecules. 2012;45:9595–603.

    Article  CAS  Google Scholar 

  26. Campbell DS. Structural characterization of vulcanizates. 11. Network-bound accelerator residues. J Appl Polym Sci. 1970;14:1409–19.

    Article  CAS  Google Scholar 

  27. Gundogan N, Okay O, Oppermann W. Swelling, elasticity and spatial inhomogeneity of poly(N,N-dimethylacrylamide) hydrogels formed at various polymer concentrations. Macromol Chem Phys. 2004;205:814–23.

    Article  CAS  Google Scholar 

  28. Orakdogen N, Okay O. Reentrant conformation transition in poly(N,N-dimethylacrylamide) hydrogels in water-organic solvent mixtures. Polymer. 2006;47:561–8.

    Article  CAS  Google Scholar 

  29. Oh H, Joo MK, Sohn YS, Jeong B. Secondary structure effect of polypeptide on reverse thermal gelation and degradation of L/DL-poly(alanine)-poloxamer-L/DL-poly(alanine) copolymers. Macromolecules. 2008;41:8204–9.

    Article  CAS  Google Scholar 

  30. Cheng Y, He C, Xiao C, Ding J, Zhuang X, Huang Y, et al. Decisive role of hydrophobic side groups of polypeptides in thermosensitive gelation. Biomacromolecules. 2012;13:2053–9.

    Article  CAS  Google Scholar 

  31. Griffin WC. Classification of surface-active agents by “HLB”. J Soc Cosmet Chem. 1949;1:311–26.

    Google Scholar 

  32. Mergny JL, Lacroix L. Analysis of thermal melting curves. Oligonucleotides. 2003;13:515–37.

    Article  CAS  Google Scholar 

  33. Jang K, Iijima K, Koyama Y, Uchida S, Asai S, Takata T. Synthesis and properties of rotaxane-cross-linked polymers using a double-stranded γ-CD-based inclusion complex as a supramolecular cross-linker. Polymer. 2017;128:379–85.

    Article  CAS  Google Scholar 

  34. Functional polymers by post-polymerization modification: concepts, guidelines and applications. Eds: Theato P, Klok HA Wiley-VCH, New York, 2012.

  35. Blasco E, Sims MB, Goldmann AS, Sumerlin BS, Barner-Kowollik C. 50th anniversary perspective: polymer functionalization. Macromolecules. 2017;50:5215–52.

    Article  CAS  Google Scholar 

  36. Gauthier MA, Gibson MI, Klok HA. Synthesis of functional polymers by post-polymerization modification. Angew Chem Int Ed. 2009;48:48–58.

    Article  CAS  Google Scholar 

  37. Nair DP, Podgórski M, Chatani S, Gong T, Xi W, Fenoli CR, et al. The thiol-Michael addition click reaction: a powerful and widely used tool in materials chemistry. Chem Mater. 2014;26:724–44.

    Article  CAS  Google Scholar 

  38. Das A, Theato P. Activated ester containing polymers: opportunities and challenges for the design of functional macromolecules. Chem Rev. 2016;116:1434–95.

    Article  CAS  Google Scholar 

  39. Sruthi PR, Anas S. An overview of synthetic modification of nitrile group in polymers and applications. J Polym Sci. 2020;58:1039–61.

    Article  CAS  Google Scholar 

  40. Sada K, Takeuchi M, Fujita N, Numata M, Shinkai S. Post-polymerization of preorganized assemblies for creating shape-controlled functional materials. Chem Soc Rev. 2007;36:415–35.

    Article  CAS  Google Scholar 

  41. As for Ref-Gel, the hydrophobic structures at the cross-linking points are sparsely located in the hydrogel, which can contribute on the UCST behaviors. For a related report, see: Taylor M. J, Tomlins P, Sahota T. S. Thermoresponsive gels. Gels, 2017; 3;4/1–31.

Download references

Acknowledgements

This work was supported by the Ogasawara Toshiaki Memorial Foundation.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan

    Namiki Komuro, Noriyuki Nakajima, Masahiro Hamada & Yasuhito Koyama

  2. Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan

    Noriyuki Nakajima, Masahiro Hamada & Yasuhito Koyama

Authors
  1. Namiki Komuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noriyuki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masahiro Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhito Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhito Koyama.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Komuro, N., Nakajima, N., Hamada, M. et al. Design and synthesis of amphiphilic alternating peptides with lower critical solution temperature behaviors. Polym J 54, 903–912 (2022). https://doi.org/10.1038/s41428-022-00639-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41428-022-00639-7

This article is cited by

Search

Advanced search

Quick links