像2/3酶抑制剂一样的赖氨酰氧化酶PXS-5153A减少了交联并改善了纤维化。,Journal of Cellular and Molecular Medicine

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像2/3酶抑制剂一样的赖氨酰氧化酶PXS-5153A减少了交联并改善了纤维化。
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2018-12-09 , DOI: 10.1111/jcmm.14074
Heidi Schilter ₁ , Alison D Findlay ₁ , Lara Perryman ₁ , Tin T Yow ₁ , Joshua Moses ₁ , Amna Zahoor ₁ , Craig I Turner ₁ , Mandar Deodhar ₁ , Jonathan S Foot ₁ , Wenbin Zhou ₁ , Angelique Greco ₁ , Amar Joshi ₁ , Benjamin Rayner _{2,

3} , Sarah Townsend _{4,

5} , Alberto Buson ₁ , Wolfgang Jarolimek ₁

Affiliation

纤维化的特征在于细胞外基质和交联蛋白（尤其是胶原蛋白和弹性蛋白）的过多沉积，从而导致组织变硬和器官功能受损。赖氨酰氧化酶是此过程中的关键角色，因为它们通过赖氨酸或羟赖氨酸的ε-氨基在胶原蛋白侧链上的氧化来引发胶原交联，随后其二聚形成不成熟，或三聚形成成熟的胶原交联。LOXL2在纤维化和癌症中的作用已得到充分证明，但是LOXL2和LOXL3在疾病过程中的特定酶功能尚不清楚。在本文中，我们描述了PXS-5153A的开发，PXS-5153A是一种基于新型机制的速效双LOXL2 / LOXL3抑制剂，可用于询问这些酶在胶原交联和纤维化模型中的作用。PXS-5153A在体外剂量依赖性地减少了LOXL2介导的胶原蛋白氧化和胶原蛋白交联。在两种肝纤维化模型中，四氯化碳或链脲佐菌素/高脂饮食诱导的PXS-5153A通过减少胶原蛋白含量和胶原蛋白交联来降低疾病的严重程度并改善肝功能。在心肌梗塞中，PXS-5153A可改善心输出量。总之，这些结果表明，由于它们在胶原蛋白交联中的关键作用，抑制LOXL2 / LOXL3的酶促活性代表了一种创新的纤维化治疗方法。PXS-5153A通过减少胶原蛋白含量和胶原蛋白交联来降低疾病严重程度并改善肝功能。在心肌梗塞中，PXS-5153A可改善心输出量。总之，这些结果表明，由于它们在胶原蛋白交联中的关键作用，抑制LOXL2 / LOXL3的酶促活性代表了一种创新的纤维化治疗方法。PXS-5153A通过减少胶原蛋白含量和胶原蛋白交联来降低疾病严重程度并改善肝功能。在心肌梗塞中，PXS-5153A可改善心输出量。总之，这些结果表明，由于它们在胶原蛋白交联中的关键作用，抑制LOXL2 / LOXL3的酶促活性代表了一种创新的纤维化治疗方法。

"点击查看英文标题和摘要"

The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis.

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

更新日期：2019-11-01

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