Abstract
To address the different types of pain different classes of medications, mainly non-steroidal anti-inflammatory drugs and narcotics (opioids), are used. The alleviation or treatment of moderate to severe pain states, in particular, commonly invokes the use of opioids. Unfortunately, their chronic administration induces various undesirable side effects, such as for example physical dependence and tolerance. Two strategies to overcome these major side effects and to prolong the antinociceptive efficiency of the applied drugs involve: a) the creation of multifunctional compounds which contain hybridized structures (Part 1), and b) the design of peptide-based hydrogels as delivery systems for the controlled-release of painkillers (Part 2).
Part 1
Combination of opioid agonist and antagonist pharmacophores in a single chemical entity has been considered and extensively investigated, but opioids have also been structurally combined with other bioactive neurotransmitters and peptide hormones that are involved in pain perception (e.g. substance P, neurotensin, cholecystokinin, cannabinoids, melanocortin ligands, etc.). Such novel chimeras (also called designed multiple ligands (DMLs) or multitarget ligands), may interact independently with their respective receptors and potentially result in more effective antinociceptive properties. The designed multiple ligands presented in this work include opioid-non-opioid (non-)peptide dimer analogs, such as for example opioid-neurokinin 1 receptor DMLs and opioid-neuropeptide FF DMLs. During the presentation, a main focus is placed on the design and biological evaluation of these multiple opioid compounds.
Part 2
To overcome the need of repeated high dose administration, hydrogels have been reported as suitable controlled drug-delivery systems. More specifically, peptide hydrogels loaded with active ingredients can liquefy during injection, followed by quick hydrogel reformation once injected. These systems present several advantages such as the protection of the drug against the enzymatic degradation by encapsulation in the hydrogel network, while maintaining the therapeutic plasma drug concentration over a long period via diffusion from the hydrogel or by degradation of the network.[1] Consequently, lower dosage and frequency of administration are possible and result in an improvement of the drug efficacy while reducing the risk of side effects. Here, a new family of short, tunable and amphipathic hexapeptide hydrogel-forming peptides was designed. In order to study their eventual therapeutic potential, the hydrogels have been used for entrapment and sustained release of opioid drugs. The in vitro drug release properties and hydrogel toxicity were, for instance, determined. Based on the best physicochemical, mechanical, and noncytotoxic properties, selected hydrogels were investigated for in vivo release of opioids. Opioid administration by subcutaneous injection and subsequent testing in the tail-flick assay (acute pain model), showed sustained antinociceptive effects over longer periods of time (up to 96 hours), as compared to drug injections in saline solutions (<3 hours).
Short Bio
Prof. Dr. Steven Ballet completed his PhD at the Vrije Universiteit Brussel (VUB, Brussels, Belgium) in 2007. Directly following his PhD training, Dr. Ballet went for a first postdoctoral stay in Australia at the University of Adelaide with Professor Andrew Abell. During this stay he applied ring closing and cross metathesis reactions on amino acid and peptide substrates. As such, dimeric but also ring closed peptide scaffolds could be obtained. More specifically, RCM was used to stabilize ('staple') the helical conformation of alpha and beta peptides. As a second postdoctoral training, Dr. Ballet went to the Institut de Recherches Cliniques de Montréal (IRCM, Montreal, Canada) for a specialized training in the opioid peptide field. Together with Prof. Peter W. Schiller, he designed bifunctional opioid ligands with dual MOR/DOR agonist profiles and hybrid opioid/non-opioid multitarget ligands. Since 2010 Dr. Ballet is appointed as a faculty member at his alma mater, where he pursues his efforts in the peptide and peptidomimetic field. Some research topics involve injectable peptide hydrogels for sustained release of bioactive peptides, the synthesis of turn/helix/loop mimetics, and transition metal-catalyzed derivatization of peptides in aqueous media.
Selected references
Guillemyn, K. et al. Bifunctional Peptide-Based Opioid Agonist−Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain. J. Med. Chem. 2016, 59, 3777.
Martin, C. et al. Controlled-release of opioids for improved pain management. Materials Today 2016, 19, 491.
Martin C. et al. Biodegradable amphipathic peptide hydrogels as extended-release system for opioid peptides. J. Med. Chem. 2018, 61, 9784.
