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作为新兴药物靶点的人几丁质酶和几丁质酶样蛋白——药物化学视角

Human chitinases and chitinase-like proteins as emerging drug targets - a medicinal chemistry perspective.

作者信息

Kurç Önder, Rähse Nick, Gohlke Holger, Cramer Jonathan

机构信息

Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute for Pharmaceutical and Medicinal Chemistry Universitätsstr. 1 40225 Düsseldorf Germany

Forschungszentrum Jülich, Institute of Bio- and Geosciences (IBG-4: Bioinformatics) Wilhelm-Johnen-Str. 52425 Jülich Germany.

出版信息

RSC Med Chem. 2025 Apr 24. doi: 10.1039/d4md01050g.

DOI:10.1039/d4md01050g
PMID:40313579
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12042104/
Abstract

Human chitinases and chitinase-like proteins (CLPs) provide the immune system with the ability to recognize or process chitin originating from chitinous pathogens. In addition to their role in host defense, most members of this protein family have evolved pleiotropic cellular effector functions broadly related to immune homeostasis, cell proliferation, and tissue remodeling. This wide-ranging ability to modulate crucial cellular processes proceeds the activation of cellular signal transduction cascades and appears to be fully independent of chitin recognition. Dysregulation of chitinase/CLP functions has been linked to a plethora of inflammatory diseases, such as allergic airway diseases and asthma, fibrosis, as well as cancer. This fact predetermines certain members of this protein family as prime targets for pharmacological intervention. Here, we provide an extensive review of medicinal chemistry efforts targeting the most widely studied members of the human chitinase/CLP family, namely acidic mammalian chitinase (AMCase), chitotriosidase (CHIT1), and chitinase-3-like protein 1 (CHI3L1/YKL-40).

摘要

人类几丁质酶和几丁质酶样蛋白（CLPs）使免疫系统具备识别或处理源自含几丁质病原体的几丁质的能力。除了在宿主防御中的作用外，该蛋白家族的大多数成员还进化出了多效性细胞效应功能，这些功能广泛涉及免疫稳态、细胞增殖和组织重塑。这种调节关键细胞过程的广泛能力先于细胞信号转导级联反应的激活，并且似乎完全独立于几丁质识别。几丁质酶/CLP功能失调与多种炎症性疾病有关，如过敏性气道疾病和哮喘、纤维化以及癌症。这一事实决定了该蛋白家族的某些成员成为药物干预的主要靶点。在此，我们对针对人类几丁质酶/CLP家族研究最广泛的成员，即酸性哺乳动物几丁质酶（AMCase）、壳三糖苷酶（CHIT1）和几丁质酶-3-样蛋白1（CHI3L1/YKL-40）的药物化学研究工作进行了全面综述。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf20/12042104/e854214729ac/d4md01050g-f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf20/12042104/68f987866388/d4md01050g-f9.jpg
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Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke.饮酒改变了血浆 YKL-40 水平对急性缺血性脑卒中患者卒中特异性死亡率的影响。
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