Tressel Sarah L, Koukos Georgios, Tchernychev Boris, Jacques Suzanne L, Covic Lidija, Kuliopulos Athan
Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, USA.
Methods Mol Biol. 2011;683:259-75. doi: 10.1007/978-1-60761-919-2_19.
G protein-coupled receptors (GPCR) are a superfamily of receptors that are vital in a wide array of physiological processes. Modulation of GPCR signaling has been an intensive area of therapeutic study, mainly due to the diverse pathophysiological significance of GPCRs. Pepducins are cell-penetrating lipidated peptides designed to target the intracellular loops of the GPCR of interest. Pepducins can function as agonists or antagonists of their cognate receptor, making them highly useful compounds for the study of GPCR signaling. Pepducins have been used to control platelet-dependent hemostasis and thrombosis, tumor growth, invasion, and angiogenesis, as well as to improve sepsis outcomes in mice. Pepducins have been successfully designed against a wide variety of GPCRs including the protease-activated receptors (PAR1, 2, 4), the chemokine receptors (CXCR1, 2, 4), the sphingosine-1-phosphate receptor (S1P3), the adrenergic receptor (ADRA1B), and have the potential to help reveal the functions of intractable GPCRs. Pharmacokinetic, pharmacodynamic, and biodistribution studies have showed that pepducins are widely distributed throughout the body except the brain and possess appropriate drug-like properties for use in vivo. Here, we discuss the delivery, pharmacology, and biodistribution of pepducins, as well as the effects of pepducins in models of inflammation, cardiovascular disease, cancer, and angiogenesis.
G蛋白偶联受体（GPCR）是一类受体超家族，在众多生理过程中至关重要。GPCR信号传导的调节一直是治疗研究的重点领域，主要是因为GPCR具有多种病理生理意义。肽导向药物（pepducins）是一种细胞穿透性脂化肽，旨在靶向目标GPCR的细胞内环。肽导向药物可以作为其同源受体的激动剂或拮抗剂，使其成为研究GPCR信号传导的非常有用的化合物。肽导向药物已被用于控制血小板依赖性止血和血栓形成、肿瘤生长、侵袭和血管生成，以及改善小鼠脓毒症的预后。肽导向药物已成功设计用于多种GPCR，包括蛋白酶激活受体（PAR1、2、4）、趋化因子受体（CXCR1、2、4）、1-磷酸鞘氨醇受体（S1P3）、肾上腺素能受体（ADRA1B），并有可能帮助揭示难治性GPCR的功能。药代动力学、药效学和生物分布研究表明，肽导向药物除了在大脑外，在全身广泛分布，并具有适用于体内使用的类药物特性。在此，我们讨论肽导向药物的递送、药理学和生物分布，以及肽导向药物在炎症、心血管疾病、癌症和血管生成模型中的作用。
