Título:
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Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects
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Autor/a:
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Gallo, Maria; Moreno, Estefanía; Defaus, Sira; Ortega-Alvaro, Antonio; Gonzalez, Angel; Robledo, Patricia; Cavaco, Marco; Neves, Vera; Castanho, Miguel A. R. B.; Casadó, Vicent; Pardo Carrasco, Leonardo; Maldonado, Rafael; Andreu Martínez, David
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Abstract:
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Altres ajuts: Rhodes Pharmaceuticals (L.P., Coventry, R.I., USA; 2016−2017), Marie Skłodowska-Curie Research and Innovation StaffExchange (call H2020-MSCA-RISE-2014, 2015−2019), and the Fundació Bancaria La Caixa (CaixaImpulse 2018 call; 2018-2020). |
Abstract:
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The activation of cannabinoid CB receptors (CBR) by Δ 9 -tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CBR activation, however, also causes cognitive impairment via the serotonin 5HT receptor (5HTR), a component of a CBR-5HTR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CBR transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CBR-5HTR 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 CBR-5HTR 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. |
Derechos:
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open access
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Uri:
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https://ddd.uab.cat/record/250419
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