Pharmaceutical modulation of the proteolytic profile of Transforming Growth Factor Beta induced protein (TGFBIp) offers a new avenue for treatment of TGFBI-corneal dystrophy
Pharmaceutical modulation of the proteolytic profile of Transforming Growth Factor Beta induced protein (TGFBIp) offers a new avenue for treatment of TGFBI-corneal dystrophy
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转化生长因子β诱导蛋白（TGFBIp）蛋白水解谱的药物调节为治疗 TGFBI 角膜营养不良提供了新途径
DOI：
10.1016/j.jare.2020.05.012
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发表时间：
2020
影响因子：
10.7
通讯作者：
J. Mehta
中科院分区：
文献类型：
--
作者：
Anandalakshmi Venkatraman;Minh;K. Pervushin;S. Ohlson;J. Mehta
角膜营养不良是一组遗传性疾病，其TGF β 1基因突变影响Bowman膜和角膜基质。突变型TGF β 1 β具有高度聚集倾向，并沉积在角膜中。根据突变的类型，蛋白质沉积可能会有所不同（淀粉样蛋白、无定形粉末状聚集体或两者的混合形式），使角膜不透明，从而降低视力。发现突变蛋白的聚集是特异性的，具有与角膜不同的独特聚集机制。据报道，突变体蛋白的蛋白水解加工与WT蛋白不同。突变蛋白的蛋白水解加工产生高度淀粉样蛋白生成肽片段。目前可供患者使用的治疗选择是与高复发率相关的组织置换手术。对于角膜营养不良患者的简单治疗选择的临床需求已经变得非常重要，以防止蛋白质聚集或溶解预先形成的聚集体。在这里，我们报告了2500化合物的筛选从Maybridge RO 3片段库使用弱亲和层析（WAC）。通过15 N-HSQC NMR分析验证来自WAC的主要命中，并鉴定了结合的特定区域。重组突变蛋白（R555 W和H572 R的第4个FAS-1结构域）与NMR分析鉴定的先导化合物一起进行胰蛋白酶有限的蛋白水解。先导化合物（M007617、RJF 00203和BTB 05094）有效延迟/防止R555 W突变体中淀粉样蛋白生成肽的产生，化合物（RJF 00203和BTB 05094）有效延迟/防止H572 R突变体中淀粉样蛋白生成肽的产生。因此，本文报道的先导化合物在进一步验证和/或修饰后可能被提议作为潜在的治疗选择，以通过抑制TGF β 1-角膜营养不良中淀粉样蛋白生成肽的形成来预防/延迟聚集。
Corneal dystrophies are a group of genetically inherited disorders with mutations in theTGFBIgene affecting the Bowman’s membrane and the corneal stroma. The mutant TGFBIp is highly aggregation-prone and is deposited in the cornea. Depending on the type of mutation the protein deposits may vary (amyloid, amorphous powdery aggregate or a mixed form of both), making the cornea opaque and thereby decreases visual acuity. The aggregation of the mutant protein is found to be specific with a unique aggregation mechanism distinct to the cornea. The proteolytic processing of the mutant protein is reported to be different compared to the WT protein. The proteolytic processing of mutant protein gives rise to highly amyloidogenic peptide fragments. The current treatment option, available for patients, is tissue replacement surgery that is associated with high recurrence rates. The clinical need for a simple treatment option for corneal dystrophy patients has become highly essential either to prevent the protein aggregation or to dissolve the preformed aggregates. Here, we report the screening of 2500 compounds from the Maybridge RO3 fragment library using weak affinity chromatography (WAC). The primary hits from WAC were validated by15N-HSQC NMR assays and specific regions of binding were identified. The recombinant mutant proteins (4th FAS-1 domain of R555W and H572R) were subjected to limited proteolysis by trypsin together with the lead compounds identified by NMR assays. The lead compounds (MO07617, RJF00203 and, BTB05094) were effective to delay/prevent the generation of amyloidogenic peptides in the R555W mutant and compounds (RJF00203 and BTB05094) were effective to delay/prevent the generation of amyloidogenic peptides in the H572R mutant. Thus the lead compounds reported here upon further validation and/or modification might be proposed as a potential treatment option to prevent/delay aggregation by inhibiting the formation of amyloidogenic peptides inTGFBI-corneal dystrophy.
DOI：
10.1016/j.bbapap.2013.10.008
发表时间：
2013-12
影响因子：
3.2
作者：
Underhaug, Jan;Koldso, Heidi;Runager, Kasper;Nielsen, Jakob Toudahl;Sorensen, Charlotte S.;Kristensen, Torsten;Otzen, Daniel E.;Karring, Henrik;Malmendal, Anders;Schiott, Birgit;Enghild, Jan J.;Nielsen, Niels Chr.
通讯作者：
Nielsen, Niels Chr.
丝氨酸蛋白酶 HtrA1 在角膜转化生长因子β诱导蛋白 (TGFBIp) 淀粉样蛋白沉积物中积累。
影响因子：
2.2
作者：
Karring,Henrik;Poulsen,EbbeToftgaard;Runager,Kasper;Thøgersen,IdaB;Klintworth,GordonK;Højrup,Peter;Enghild,JanJ
通讯作者：
Enghild,JanJ
影响因子：
3.4
作者：
Karring H;Runager K;Valnickova Z;Thøgersen IB;Møller-Pedersen T;Klintworth GK;Enghild JJ
通讯作者：
Enghild JJ