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Papers of the Week

Papers: 24 Apr 2021 - 30 Apr 2021

Pharmacology/Drug Development

2021 Apr 22

J Med Chem

Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects.


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
J Med Chem. 2021 Apr 22.
PMID: 33887904.


The activation of cannabinoid CB receptors (CBR) by Δ-tetrahydrocannabinol (THC), the main component of , induces analgesia. CBR activation, however, also causes cognitive impairment 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.