Poster Presentation International Peptide Symposium 2023

Harnessing the Power of Photoinitiated Thiol–ene “click” Reaction for the Efficient Synthesis of S-Lipidated Collagen Model Peptide Amphiphiles (#206)

C.J. Aguilar 1 , Mak Sarwar 2 3 , Sujay Prabakar 4 , Wen-Kai Zhang 4 , Paul W. R. Harris 1 3 5 , Margaret A. Brimble 1 3 5 , Iman Kavianinia 1 3 5
  1. School of Chemical Sciences, University of Auckland, Auckland, New Zealand
  2. Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
  3. Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
  4. Leather and Shoe Research Association, Palmerston North, New Zealand
  5. School of Biological Sciences, University of Auckland, Auckland, New Zealand

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Collagen, a remarkable biomolecule, can self-assemble into intricately structured triple helices, making it a key cellular matrix component. Researchers have sought to create collagen protein mimics known as collagen model peptides (CMPs) to explore its folding and stability. These short collagen model peptides hold promising potential in various applications, including drug delivery, biomaterials, cosmetics, and tissue engineering. However, developing new CMPs may pose challenges such as low thermal stability and poor water solubility, limiting their utilisation in specific applications.1 One approach to address the low thermal stability of CMPs involves the incorporation of lipid moieties, known to enhance both thermal stability and the folding rate of collagen triple helices.2 Nevertheless, the hydrophobic nature of the lipidated constructs often hampers their solubility. To overcome this challenge, we successfully employed a novel strategy by reacting a known collagen mimetic peptide (Gly-Pro-Hyp)3-[IV-H1]-(Gly-Pro-Hyp)3 with 2-iminothiolane (Traut's Reagent).3 This reaction yielded a terminal thiol group and a positively charged amidinium moiety through nucleophilic attack and transient ring opening.4 Subsequently, the thiol-functionalised collagen mimetic peptide underwent a photoinitiated thiol-ene "click" reaction, forming an S-lipidated peptide amphiphile.5 The resulting S-lipidated CMP exhibited not only stable triple helices but also demonstrated enhanced bioactivity when compared to non-lipidated congeners. These findings further emphasise the tremendous potential of our strategy in developing novel CMPs for biomedical applications.

 

  1. Yang, J.; Ding, C.; Tang, L.; Deng, F.; Yang, Q.; Wu, H.; Chen, L.; Ni, Y.; Huang, L.; Zhang, M. Novel Modification of Collagen: Realizing Desired Water Solubility and Thermostability in a Conflict-Free Way. ACS Omega 2020, 5 (11), 5772–5780. https://doi.org/10.1021/acsomega.9b03846.
  2. Egli, J.; Esposito, C.; Müri, M.; Riniker, S.; Wennemers, H. Influence of Lipidation on the Folding and Stability of Collagen Triple Helices—An Experimental and Theoretical Study. J. Am. Chem. Soc. 2021, 143 (15), 5937–5942. https://doi.org/10.1021/jacs.1c01512.
  3. Yu, Y.-C.; Tirrell, M.; Fields, G. B. Minimal Lipidation Stabilizes Protein-Like Molecular Architecture. J. Am. Chem. Soc. 1998, 120 (39), 9979–9987. https://doi.org/10.1021/ja981654z.
  4. Traut, R. R.; Bollen, A.; Sun, T.-T.; Hershey, J. W. B.; Sundberg, J.; Pierce, L. R. Methyl 4-Mercaptobutyrimidate as a Cleavable Crosslinking Reagent and Its Application to the Escherichia Coli 30S Ribosome. Biochemistry 1973, 12 (17), 3266–3273. https://doi.org/10.1021/bi00741a019.
  5. Yang, S.-H.; Harris, P. W. R.; Williams, G. M.; Brimble, M. A. Lipidation of Cysteine or Cysteine-Containing Peptides Using the Thiol-Ene Reaction (CLipPA). Eur. J. Org. Chem. 2016, 2016 (15), 2608–2616. https://doi.org/10.1002/ejoc.201501375.