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http://hdl.handle.net/2445/178408
Title: | Orally active peptide vector allows using cannabis to fight pain while avoiding side effects |
Author: | Gallo, Maria 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 Pèptids Cannabis Pain treatment Peptides |
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: https://doi.org/10.1021/acs.jmedchem.1c00484 |
It is part of: | Journal of Medicinal Chemistry, 2021, vol. 64, num. 10, p. 6937-6948 |
URI: | http://hdl.handle.net/2445/178408 |
Related resource: | https://doi.org/10.1021/acs.jmedchem.1c00484 |
ISSN: | 0022-2623 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
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711916.pdf | 6.93 MB | Adobe PDF | View/Open |
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