Cauwenbergh, Thibault; Dallagnol, Juliana C; Chatenet, David 
ORCID: https://orcid.org/0000-0002-7270-4328; Martin, Charlotte et Ballet, Steven
(2024).
Optimization of antivasoconstricting UT-II-derived biogels
In: 37th European Peptide Symposium 14th International Peptide Symposium, August 25-29, 2024, Florence, Italy.
Résumé
Over the past years, we have developed, optimized, and extensively
tested the amphipathic hexapeptide hydrogel sequence H-Phe-GlnPhe-Gln-Phe-Lys-NH2 for drug delivery applications, among others.
[1] Its easy synthesis and high degree of tunability have rendered this
self-assembling lead peptide exceptionally versatile in the sustained
release of a diverse range of (therapeutic) molecules. In an attempt to
further prolong the drug release using our hydrogels, we previously
developed a variety of hydrogel-drug conjugates templated on our
lead hexapeptide. [2] These hydrogels, designated as biogels, were
successfully applied in the sustained release of opioid peptides
in vivo.
With the ultimate aim of countering frequent drug administration in a
broader sense, we selected the Urotensin-II receptor (UT-IIR) as an
interesting target for further concept development. Urotensin-II
(UT-II), a cyclic somatostatin-like undecapeptide, is one of the most
potent natural vasoconstrictors and is believed to be involved in various cardiovascular and other pathologies. Based on the findings of an
extensive SAR- and truncation study reported in the literature, [3] we
developed two distinct, linear biogel designs, formally denoted as the
β-strand and β-hairpin models. The former model consists of conjugating the UT-II core pharmacophore (i.e., H-Phe-Trp-Lys-Tyr-OH) directly to the N-terminus of our hexapeptide hydrogelator, while the
latter consists of flanking the pharmacophore by two hydrogelator
tails to induce a type II' β-turn in the pharmacophore, a feature which
is deemed necessary for receptor recognition. Alongside these linear
lead peptides, disulfide-bridged analogues were synthesized to assess
the importance of the disulfide bridge in receptor binding. To enhance
the activity of the designed conjugate hydrogels and compete with
the native UT-II peptides, a SAR study was performed on the pharmacophoric Tyr4
-residue. In addition, to conserve the integrity of the
pharmacophore and to guarantee long-lasting activity, proteolytic
resistance was enhanced using various approaches. The work
reported here puts a focus on both hydrogel and pharmacophore optimization in the search for a performant and long-acting antihypertensive hydrogel-drug conjugate.
References
1. Martin, C.; Oyen, E.; Van Wanseele, Y. et al. Mater. Today Chem.
2017, 3, 49-59.
2. Martin, C.; Dumitrascuta, M.; Mannes, M. et al. J. Med. Chem.
2018, 61, 9784-9789.
3. Bandholtz, S.; Erdmann, S.; von Hacht, J. L. et al. J. Med. Chem.
2016, 59, 10100-10112.
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Journal of Peptide Science 30(Suppl. 2):207-208 Meeting Abstract: 165-P1 Affiche scientifique |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 06 nov. 2024 04:41 |
| Dernière modification: | 06 nov. 2024 04:41 |
| URI: | https://espace.inrs.ca/id/eprint/16108 |
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