TY - JOUR
T1 - Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects
AU - Gallo, Maria
AU - Moreno, Estefanía
AU - Defaus, Sira
AU - Ortega-Alvaro, Antonio
AU - Gonzalez, Angel
AU - Robledo, Patricia
AU - Cavaco, Marco
AU - Neves, Vera
AU - Castanho, Miguel A R B
AU - Casadó, Vicent
AU - Pardo, Leonardo
AU - Maldonado, Rafael
AU - Andreu, David
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/4/22
Y1 - 2021/4/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106530090&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00484
DO - 10.1021/acs.jmedchem.1c00484
M3 - Article
C2 - 33887904
SN - 0022-2623
VL - 64
SP - 6937
EP - 6948
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -