甲状旁腺激素失活:对抗甲状旁腺功能亢进药物发现的观点。

IF 2.4 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Amit Kumar, Jochen Balbach
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引用次数: 2

摘要

荷尔蒙的协调在人体内受到严格的调节,从而调节着人的生理机能。甲状旁腺激素(PTH)是内分泌系统的一员,调节人体内钙和磷酸盐的水平。在非生理条件下,由于外部或内部因素,甲状旁腺激素水平会上调(甲状旁腺功能亢进)或下调(甲状旁腺功能低下)。在甲状旁腺功能亢进的情况下,PTH升高会刺激存在于骨骼、肾脏和肠道中的细胞受体,从而增加血钙水平,导致钙沉积。这最终会导致各种症状,包括肾结石。目前,还没有已知的药物直接针对甲状旁腺激素以抑制其功能。因此,寻找新的小分子或任何其他手段可以调节甲状旁腺激素的功能是非常有趣的。PTH的分子信号传导始于将其n端与g蛋白偶联的PTH1/2受体结合。因此,任何影响甲状旁腺激素n端的干预措施都可能是治疗甲状旁腺功能亢进的主要候选药物。作为概念验证,有多种可能通过(i)小分子,(ii) n端PTH磷酸化,(iii)纤维形成和(iv)残基特异性突变来抑制分子PTH功能。这些修饰使甲状旁腺激素进入非活性状态,本文将对此进行详细讨论。我们预计,探索影响甲状旁腺激素n端的小分子或其他方法可能是治疗甲状旁腺功能亢进的主要候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inactivation of Parathyroid Hormone: Perspectives of Drug Discovery to Combating Hyperparathyroidism.

Hormonal coordination is tightly regulated within the human body and thus regulates human physiology. The parathyroid hormone (PTH), a member of the endocrine system, regulates the calcium and phosphate level within the human body. Under non-physiological conditions, PTH levels get upregulated (hyperparathyroidism) or downregulated (hypoparathyroidism) due to external or internal factors. In case of hyperparathyroidism, elevated PTH stimulates cellular receptors present in the bones, kidneys, and intestines to increase the blood calcium level, leading to calcium deposition. This eventually causes various symptoms, including kidney stones. Currently, there is no known medication that directly targets PTH in order to suppress its function. Therefore, it is of great interest to find novel small molecules or any other means that can modulate PTH function. The molecular signaling of PTH starts by binding its N-terminus to the G-protein coupled PTH1/2 receptor. Therefore, any intervention that affects the N-terminus of PTH could be a lead candidate for treating hyperparathyroidism. As a proof-of-concept, there are various possibilities to inhibit molecular PTH function by (i) a small molecule, (ii) N-terminal PTH phosphorylation, (iii) fibril formation and (iv) residue-specific mutations. These modifications put PTH into an inactive state, which will be discussed in detail in this review article. We anticipate that exploring small molecules or other means that affect the N-terminus of PTH could be lead candidates in combating hyperparathyroidism.

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来源期刊
Current molecular pharmacology
Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
4.90
自引率
3.70%
发文量
112
期刊介绍: Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.
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