泛素特异性蛋白酶30 (USP30) 的药物开发前景

Categories:最新消息
Author:华讯知识产权
Origin:
Time of issue:2019-05-10 18:02
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(Summary description)泛素特异性蛋白酶(ubiquitin-specificprocessingpeptidase,USPs)归属于去泛素化酶(deubiquitinatingenzymes,DUBs)，是蛋白酶超家族的一员，半胱氨酸蛋白酶的异构体之一，主要作用于泛素蛋白酶体系统中被泛素化的蛋白质，调节细胞的生长发育、调节细胞周期、调节细胞信号转导等。泛素特异性蛋白酶30(Ubquitin-specificprotea

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泛素特异性蛋白酶30 (USP30) 的药物开发前景

Categories:最新消息
Author:华讯知识产权
Origin:
Time of issue:2019-05-10 18:02
Views:

Information

泛素特异性蛋白酶(ubiquitin-specific processing peptidase, USPs)归属于去泛素化酶(deubiquitinating enzymes, DUBs)，是蛋白酶超家族的一员，半胱氨酸蛋白酶的异构体之一，主要作用于泛素蛋白酶体系统中被泛素化的蛋白质，调节细胞的生长发育、调节细胞周期、调节细胞信号转导等。

泛素特异性蛋白酶30 (Ubquitin-specific protease 30, USP30)是去泛素化酶家族中的一员，主要定位在线粒体外膜，是一种半胱氨酸蛋白酶。研究表明USP30参与了细胞内线粒体形态的调控，后续研究发现USP30可以使PARK2以及PINK1驱动的线粒体自噬被逆转，PARK2作为泛素连接酶标记损伤的线粒体使其被清除，而USP30作为去泛素化酶可以去除泛素标签从而抑制线粒体自噬，抑制USP30也有望用于治疗帕金森症。

目前已经有多家公司开展了USP30抑制剂的研发，Komander已经解析了人源USP30的结构(PDB ID: 5OHK, 5OHN, 5OHP)：USP30的催化结构域中最关键的催化三联体是Cys77-His452-Ser477，不同于USP家族中常见的Cys-His-Asp/Asn三联体。

国内USP30抑制剂的研究进展

中国科学院昆明植物研究所郝小江等人报道了一种USP30的抑制剂：二萜衍生物15-oxospiramilactone (S3)，这也是目前唯一一个天然产物来源的USP30抑制剂，S3可以抑制去泛素化，从而增强线粒体的膜蛋白MFfn1/2的活性、促进线粒体融合。值得注意的是，其申报的专利CN103360358B内容是以15-oxospiramilactone (S3)的衍生物作为Wnt信号通路抑制剂在制备抗肿瘤药物中的应用。

公开号	专利名称	申请日	公开/授权日
CN103360358B	15-氧代绣线菊内酯衍生物及其制备方法和应用	2013-07-17	2015-03-18
US10112918	15-oxospiramilactone derivatives, preparation method and uses thereof	2014-04-21	2018-10-30
WO2014169711A1	15-oxospiramilactone derivatives, preparation method therefor, and uses thereof	2014-04-21	2014-10-23

药企的USP30抑制剂研发进展

Mission Therapeutics是由剑桥大学Steve Jackson教授等人于2011年联合创办的制药公司，致力于用小分子抑制剂选择性地靶向去泛素化酶（DUB），以有效治疗患有严重和危及生命的疾病患者，该公司目前聚焦的靶点主要是USP4、USP7、USP30和UCHL1，其中USP30抑制剂项目主要聚焦线粒体相关疾病、帕金森症以及外周疾病（如肾纤维化等疾病）。

Mission Therapeutics也是目前USP30抑制剂研发大军的绝对主力，已公开与USP30相关的专利有数十项。专利中已经公开报道了USP30抑制剂的代表性化合物，但是目前该公司报道的化合物中并未详细介绍其IC₅₀等关键数据，仅有粗略的活性数据范围。

公开号	专利名称	申请日	公开日	同族
WO2016156816A1	1-cyano-pyrrolidine compounds as USP30 inhibitors	2016-03-24	2016-10-06	AU, BR, CA, CN, CO, EP, GB, HK, IL, IN, JP, KR, MX, SG, US
WO2017009650A1	Cyanopyrrolidines as dub inhibitors for the treatment of cancer	2016-07-14	2017-01-19	CN, EP, JP, GB, US
WO2017093718A1	1-cyano-pyrrolidine derivatives as inhibitors of USP30.	2016-11-29	2017-06-08	CN, EP, JP, GB
WO2017103614A1	Novel Compounds	2016-12-16	2017-06-22	AU, BR, CA, CN, CO, EP, GB, IL, IN, JP, KR, MX, SG
WO2017109488A8	Cyanopyrrolidine derivatives as inhibitors for dubs	2016-12-21	2017-09-14	CN, EP, JP, GB, US
WO2017141036A1	Novel compounds	2017-02-16	2017-08-24	CN, EP, JP, GB, US
WO2017163078A8	1-cyano-pyrrolidine derivatives as dub inhibitors	2017-03-23	2017-12-28	CN, EP, GB
WO2018060689A1	Cyanopyrrolidine derivatives with activity as inhibitors of USP30	2017-09-27	2018-04-05	GB
WO2018060691A1	Cyano-subtituted heterocycles with activity as inhibitors of USP30	2017-09-27	2018-04-05	GB, TW
WO2018060742A1	Cyanopyrrolidine derivatives with activity as inhibitors of USP30	2017-10-02	2018-04-05	GB
WO2018065768A1	Cyano-substituted heterocycles with activity as inhibitors of USP30	2017-10-04	2018-04-12	AR, GB, TW
WO2018220355A1	Sulfonamide-substituted cyanopyrrolidines with activity as dub inhibitors	2018-05-30	2018-12-06	GB
WO2018234775A1	Substituted cyanopyrrolidines with activity as dub inhibitors	2018-06-19	2018-12-27	GB

近日，另一家制药公司Forma Therapeutics也公开了一项USP30抑制剂的专利申请WO2019071073A1。与Mission Therapeutics类似的是，其专利中USP30的抑制活性并未给出具体数值，仅有粗略的范围。

公开号	专利名称	申请日	公开日	同族
WO2019071073A1	Inhibiting ubiquitin specific peptidase 30	2018-10-05	2019-04-11	---

结语

SP30作为去泛素化酶大家族的一员，其生物学机制的研究仍然不是很多，但由于其定位在线粒体，这一特性注定其与线粒体相关疾病有千丝万缕的关系。目前，天然产物来源的USP30仅有一例报道，且后续进展不明朗，而几家制药公司所报道的USP30抑制剂研究尚不够深入，但USP30的晶体结构已经得到解析，这将为USP30抑制剂的设计提供更多的便利。随着USP30在不同疾病中作用的日渐明晰，USP30抑制剂的研发有可能会像USP7抑制剂的研发一样进入激烈竞争的态势。

参考资料：https://med.sina.com/article_detail_103_2_65170.html

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