Poster Presentation The 16th Australian Peptide Conference 2025

Tackling Heart Failure: On the Development of Potent Long-Acting UT-II-Derived Biogels (#210)

Thibault Cauwenbergh 1 , Juliana C. C. Dallagnol 2 , David Chatenet 2 , Charlotte Martin 1 , Steven Ballet 1
  1. Research Group of Organic Chemistry (ORGC), Vrije Universiteit Brussel, Brussels, Belgium
  2. Institut Armand-Frappier, Institut National des Recherches Scientifiques (INRS), Québec, Canada

 

Over the past few decades, peptide hydrogels have secured an established position in extended-release disease treatment, owing to their straightforward synthesis, high tuneability and biocompatibility. We have developed, optimized and extensively tested our own amphipathic hexapeptide hydrogel sequence H-Phe-Gln-Phe-Gln-Phe-Lys-NH2 for drug delivery applications, among others.1 Its easy synthesis and high degree of tuneability have rendered this self-assembling lead peptide exceptionally versatile in the sustained release of a diverse range of (therapeutic) molecules. To prolong the drug release, we previously developed a variety of hydrogel-drug conjugates templated on this lead hexapeptide.2 These hydrogels, designated as biogels, were successfully applied in the sustained release of opioid peptides in vivo. With the aim of countering frequent drug administration in a broader sense, we selected the G protein-coupled Urotensin-II receptor (UTR) as an interesting target for additional concept development. Its endogenous ligand, the cyclic somatostatin-like undecapeptide Urotensin-II (UTII), is one of the most potent natural vasoconstrictors and is believed to be involved in various cardiovascular and other pathologies.3 Based on the findings of an extensive SAR and truncation study reported in literature,4 we developed two distinct biogel designs, formally denoted as the β-strand- and β-hairpin-model. The former model consists of conjugating the UTII pharmacophore (i.e. H-Phe-Trp-Lys-Tyr-OH) directly to the N-terminus of our hexapeptide hydrogelator. The latter model, on the other hand, consists of flanking the pharmacophore by two hydrogelator tails, potentially favoring a β-turn formation in the pharmacophore, a feature which is deemed necessary for receptor recognition.5 The UTR efficacy of these designs was evaluated using a BRET bioassay and modifications were made to enhance both the activity and stability of the gelating sequences. The work presented here puts a focus both on hydrogel and pharmacophore optimization in search for a performant and long-acting hydrogel-drug conjugate for the treatment of heart failure and other related cardiovascular pathologies.

  1. a) C. Martin, E. Oyen, J. Mangelschots et al., Med. Chem. Comm. 2016, 7, 542–549. b) C. Martin, E. Oyen, Y. Van Wanseele et al. Mater. Today Chem. 2017, 3, 49–59. c) J. Heremans, R. M. Awad, J. Bridoux et al., Eur. J. Pharm. Biopharm. 2024, 196, 114183.
  2. C. Martin, M. Dumitrascuta, M. Mannes et al., J. Med. Chem. 2018, 61, 9784–9789.
  3. D. Pearson, J. E. Shively, B. R. Clark et al., Proc. Natl. Acad. Sci. U. S. A. 1980, 77, 5021−5024.
  4. S. Bandholtz, S. Erdmann, J. L. von Hacht et al., J. Med. Chem. 2016, 59, 10100–10112.
  5. P. Grieco, A. Carotenuto, P. Campglia et al., J. Med. Chem. 2009, 52, 3927–3940.