Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.
Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.
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抗体扩大了血管紧张素受体药理学的范围。
DOI：
10.1101/2023.08.23.554128
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kruse,AndrewC
中科院分区：
文献类型：
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作者：
Skiba,MeredithA;Sterling,SarahM;Rawson,Shaun;Gilman,MorganSA;Xu,Huixin;Nemeth,GenevieveR;Hurley,JosephD;Shen,Pengxiang;Staus,DeanP;Kim,Jihee;McMahon,Conor;Lehtinen,MariaK;Wingler,LauraM;Kruse,AndrewC
G蛋白偶联受体（GPCR）是人体生理学的关键调节因子，也是许多小分子研究化合物和治疗药物的靶点。虽然这些配体中的大多数以高亲和力结合其靶GPCR，但选择性通常在受体、组织和细胞水平上受到限制。抗体具有解决这些限制的潜力，但它们作为GPCR配体的性质仍然很难表征。在这里，使用蛋白质工程，药理学测定和结构研究，我们开发母体选择性重链抗体（“纳米抗体”）拮抗剂对血管紧张素II I型受体，并揭示其受体拮抗作用的不寻常的分子基础。我们进一步表明，我们的纳米抗体可以同时结合到血管紧张素II I型受体与特定的小分子拮抗剂，并证明配体的选择性可以很容易地调整。我们的工作表明，抗体片段可以表现出丰富和可进化的药理学，证明了它们作为下一代GPCR调节剂的潜力。
G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody (‘nanobody’) antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.