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

Gallo Maria; Moreno Estefania; Defaus Sira; Ortega-Alvaro Antonio; Gonzalez Angel; Robledo Patricia; Cavaco Marco; Neves Vera; Castanho Miguel A. R. B.; Casado Vicent; Pardo Leonardo; Maldonado Rafael; Andreu David

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

机译：口服活性肽矢量允许使用大麻避免副作用的同时对抗疼痛

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The activation of cannabinoid CB1 receptors (CB1R) by Delta(9)-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT(2A) receptor (5HT(2A)R), a component of a CB1R-5HT(2A)R 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-5HT(2A)R 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-5HT(2A)R 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.

机译：大麻的主要成分δ（9）-四氢大麻酚（THC）激活大麻素CB1受体（CB1R）可诱导镇痛。然而，CB1R激活也会通过5-羟色胺5HT（2A）受体（5HT（2A）R）引起认知障碍，5HT（2A）R是CB1R-5HT（2A）R异聚体的一个组成部分，对大麻素的治疗用途构成了严重障碍。我们已经证明，与细胞穿透序列（CPP）融合的复制CB1R跨膜（TM）螺旋5和6的肽可以改变CB1R-5HT（2A）R异聚体的结构，避免THC认知损伤，同时保留镇痛作用。在这里，我们报告了通过（i）缩短TM5、TM6和CPP序列，而不丧失干扰CB1R-5HT（2A）R异聚体的能力，以及（ii）广泛的序列重塑以实现蛋白酶抗性和血脑屏障穿透，将这些原型优化为类药物先导。我们的努力最终确定了一种基于大麻的疼痛管理的理想候选者，一种口服活性16残基肽保留THC诱导的镇痛。

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来源
《Journal of Medicinal Chemistry》 |2021年第10期|共12页
作者
Gallo Maria; Moreno Estefania; Defaus Sira; Ortega-Alvaro Antonio; Gonzalez Angel; Robledo Patricia; Cavaco Marco; Neves Vera; Castanho Miguel A. R. B.; Casado Vicent; Pardo Leonardo; Maldonado Rafael; Andreu David;
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作者单位

Univ Pompeu Fabra Dept Expt &

Hlth Sci Barcelona 08003 Spain;

Univ Barcelona Inst Biomed Dept Biochem &

Mol Biomed Barcelona 08028 Spain;

Univ Pompeu Fabra Dept Expt &

Hlth Sci Barcelona 08003 Spain;

Univ Pompeu Fabra Dept Expt &

Hlth Sci Barcelona 08003 Spain;

Univ Autonoma Barcelona Fac Med Unitat Bioestadist Lab Med Computac Bellaterra 08193 Spain;

IMIM Hosp Mar Res Inst Integrat Pharmacol &

Syst Neurosci Barcelona 08003 Spain;

Univ Lisbon Fac Med Inst Med Mol P-1649028 Lisbon Portugal;

Univ Lisbon Fac Med Inst Med Mol P-1649028 Lisbon Portugal;

Univ Lisbon Fac Med Inst Med Mol P-1649028 Lisbon Portugal;

Univ Barcelona Inst Biomed Dept Biochem &

Mol Biomed Barcelona 08028 Spain;

Univ Autonoma Barcelona Fac Med Unitat Bioestadist Lab Med Computac Bellaterra 08193 Spain;

Univ Pompeu Fabra Dept Expt &

Hlth Sci Barcelona 08003 Spain;

Univ Pompeu Fabra Dept Expt &

Hlth Sci Barcelona 08003 Spain;

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正文语种 eng
中图分类药学;
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Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects

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