Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis.
Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis.
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DOI：
10.1038/s41467-022-33148-5
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发表时间：
2022-09-22
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
疤痕是皮肤损伤的终生后果，疤痕僵硬和外观不佳会给恢复正常生活带来身体和心理障碍。赖氨酰氧化酶是在疤痕形成和维持中发挥关键作用的酶家族。赖氨酰氧化酶可稳定疤痕组织的主要成分胶原蛋白，并促进疤痕硬度和外观。在这里，我们描述了不可逆赖氨酰氧化酶抑制剂 PXS-6302 的开发和表征。 PXS-6302 非常适合皮肤治疗，作为霜剂使用时很容易渗透皮肤并消除赖氨酰氧化酶活性。在损伤和纤维化的小鼠模型中，局部应用可减少胶原沉积和交联。在猪损伤模型中，损伤后局部应用 PXS-6302 还可显着改善疤痕外观，而不降低组织强度。因此，PXS-6302 代表了一种有前途的改善疤痕形成的治疗方法，在其他纤维化疾病中具有潜在更广泛的应用。疤痕是皮肤中过量胶原蛋白引起的一个严重问题。作者在这里开发了一种外用药物，可以降低胶原蛋白的稳定性，并改善临床前模型中的疤痕外观和硬度。
Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases. Scars are a significant problem caused by excess collagen in the skin. Here the authors develop a topical drug that reduces collagen stability and leads to improved scar appearance and stiffness in preclinical models.
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影响因子：
3.9
作者：
Clemons, T. D.;Bradshaw, M.;Toshniwal, P.;Chaudhari, N.;Stevenson, A. W.;Lynch, J.;Fear, M. W.;Wood, F. M.;Iyer, K. Swaminathan
通讯作者：
Iyer, K. Swaminathan
影响因子：
4.8
作者：
REISER, K;MCCORMICK, RJ;RUCKER, RB
通讯作者：
RUCKER, RB
DOI：
10.1016/j.jmbbm.2014.07.008
发表时间：
2015-12
影响因子：
3.9
作者：
Depalle B;Qin Z;Shefelbine SJ;Buehler MJ
通讯作者：
Buehler MJ
影响因子：
7.3
作者：
Jarnicki, A. G.;Schilter, H.;Hansbro, P. M.
通讯作者：
Hansbro, P. M.
影响因子：
2.9
作者：
Kieran, Ingrid;Knock, Amanda;Ferguson, Mark
通讯作者：
Ferguson, Mark