Orally active peptide vector allows using cannabis to fight pain while avoiding side effects
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- dc.contributor.author Gallo, María, 1989-
- dc.contributor.author Moreno, Estefanía
- dc.contributor.author Defaus, Sira
- dc.contributor.author Ortega Alvaro, Antonio
- dc.contributor.author Gonzalez, Angel
- dc.contributor.author Robledo, Patricia, 1958-
- dc.contributor.author Cavaco, Marco
- dc.contributor.author Neves, Vera
- dc.contributor.author Castanho, Miguel A.R.B.
- dc.contributor.author Casadó, Vicent
- dc.contributor.author Pardo Carrasco, Leonardo
- dc.contributor.author Maldonado, Rafael, 1961-
- dc.contributor.author Andreu Martínez, David
- dc.date.accessioned 2022-01-25T07:29:43Z
- dc.date.available 2022-01-25T07:29:43Z
- dc.date.issued 2021
- dc.description.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.
- dc.description.sponsorship Rhodes Pharmaceuticals (L.P., Coventry, R.I., USA; 2016–2017), Marie Skłodowska-Curie Research and Innovation Staff Exchange (call H2020-MSCA-RISE-2014, 2015–2019), the Spanish Ministry of Economy and Innovation with FEDER funds (SAF2017-87629-R, PID2019-109240RB-I00), and the Fundació Bancària La Caixa (CaixaImpulse 2018 call; 2018–2020).
- dc.format.mimetype application/pdf
- dc.identifier.citation Gallo M, Moreno E, Defaus S, Ortega-Alvaro A, Gonzalez A, Robledo P, Cavaco M, Neves V, Castanho MARB, Casadó V, Pardo L, Maldonado R, Andreu D. Orally active peptide vector allows using cannabis to fight pain while avoiding side effects. J Med Chem. 2021;64(10):6937-48. DOI: 10.1021/acs.jmedchem.1c00484
- dc.identifier.doi http://dx.doi.org/10.1021/acs.jmedchem.1c00484
- dc.identifier.issn 0022-2623
- dc.identifier.uri http://hdl.handle.net/10230/52304
- dc.language.iso eng
- dc.publisher American Chemical Society (ACS)
- dc.relation.ispartof J Med Chem. 2021;64(10):6937-48
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-87629-R
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-109240RB-I00
- dc.rights © 2021 American Chemical Society. This work is licensed under a Creative Commons Attribution 4.0 International License
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/4.0/
- dc.title Orally active peptide vector allows using cannabis to fight pain while avoiding side effects
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion