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Title: Orally active peptide vector allows using cannabis to fight pain while avoiding side effects
Author: Gallo, Mariaa
Moreno Guillén, Estefanía
Defaus, Sira
Ortega-Alvaro, Antonio
Gonzalez, Angel
Robledo, Patricia
Cavaco, Marco
Neves, Vera
Castanho, Miguel A.R.B.
Casadó, Vicent
Pardo, Leonardo
Maldonado, Rafael
Andreu, David
Keywords: Cànnabis
Tractament del dolor
Pain treatment
Issue Date: 22-Apr-2021
Publisher: American Chemical Society
Abstract: The activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R−5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB1R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB1R−5HT2AR heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB1R−5HT2AR heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood−brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medicinal Chemistry, 2021, vol. 64, num. 10, p. 6937-6948
Related resource:
ISSN: 0022-2623
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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