10 min Rapid Fire International Peptide Symposium 2023

Peptide DRT-017 prevents cognitive impairment associated to medical cannabis pain management (#34)

Maria Gallo 1 , Sira Defaus 1 , Beltrán Alvarez-Perez 1 , Estefania Moreno 2 , Vicent Casadò 2 , Leonardo Pardo 3 , Miguel Castanho 4 , Rafael Maldonado 1 , David Andreu 1
  1. Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Catalonia, Spain
  2. Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain
  3. Computational Medicine, Autonomous University of Barcelona, Bellaterra, Catalonia, Spain
  4. Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal

The main psychoactive component in Cannabis sativa, Δ⁹-tetrahydrocannabinol (THC), produces useful pharmacological effects such as analgesia by activation of the cannabinoid CB1 receptor (CB1R), a GCPR located mainly in the CNS. There is strong evidence that CB1R can form heterodimer complexes with the serotonin 5HT2A receptor (5HT2AR) that lead to new functional outcomes. We have shown that THC co-activation of the CB1R-5HT2AR heteromer underpins the adverse cognitive effects that constitute the main drawback to the potential use of THC as an analgesic.1 In this context, we have devised a novel therapeutic approach aimed at splitting the CB1R-5HT2AR heterodimer, allowing selective THC activation of CB1R, hence dissociating therapeutic from unwanted side effects. Peptides reproducing the CB1R transmembrane (TM) helices 5 and 6 involved in CB1R-5HT2AR dimerization, when fused to a cell-penetrating peptide, can reach and disrupt heterodimer complex formation.1 Such peptides, named TM5 and TM6, were however unfit for therapeutic use due to their peptide-intrinsic inadequate pharmacokinetics.2 We now report how, starting from those non-druggable CB1R-5HT2AR heterodimer-splitting peptides, we have developed DRT-017 (EU Patent WO/2021/064165, PCT/EP2020/077642), a small (16-residue) fully druggable, protease-resistant, orally available, non-immunogenic peptide that crosses the blood-brain barrier and blocks heterodimer formation both in vitro and in vivo.3 As expected, heterodimer disruption prevents the undesirable effects of cannabinoids (e.g., memory deficit) but preserves THC-linked analgesia under both acute and chronic conditions in mice.3 Hence DRT-017 is a first-in-class peptide lead capable of successfully preventing cognitive side effects in medical Cannabis users while maintaining pain relief.

  1. Viñals, X. et al. Cognitive impairment induced by Δ⁹- tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol. 13, 1–40 (2015).
  2. Gallo, M., Defaus, S. & Andreu, D. Disrupting GPCR Complexes with Smart Drug-like Peptides. Pharmaceutics 14, (2022).
  3. Gallo, M. et al. Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects. J. Med. Chem. 64, 6937-6948 (2021).