Structure-Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides.
Structure-Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides.
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DOI：
10.1021/acs.jmedchem.0c01520
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发表时间：
2020-11-12
影响因子：
7.3
通讯作者：
Lin G
中科院分区：
文献类型：
--
作者：
Zhan W;Singh PK;Ban Y;Qing X;Ah Kioon MD;Fan H;Zhao Q;Wang R;Sukenick G;Salmon J;Warren JD;Ma X;Barrat FJ;Nathan CF;Lin G
免疫蛋白酶体(I-20S)已成为自身免疫性和炎症性疾病以及血液系统恶性肿瘤的治疗靶点。抑制I-20S的胰凝乳酶β5I亚基在体外抑制T细胞激活、B细胞增殖和树突状细胞分化，并抑制自身免疫性疾病和同种异体移植排斥反应的动物模型中的免疫反应。然而，对免疫细胞的细胞毒性伴随着共价反应性β5I抑制剂的使用，其对构成蛋白酶体(c-20s)的活性随着暴露时间的增加而累积。在这里，我们报道了一类非共价蛋白酶体抑制剂的构效关系研究，这些抑制剂具有皮摩尔活性和对I-20S的数千倍于C-20S的选择性。此外，这些抑制物对β5i比I-20s和c-20s的其他5个活性亚基具有特异性，为研究β5i在免疫应答中的功能提供了有用的工具。这些化合物在抑制人类T细胞激活方面的效力表明，它们可能具有治疗潜力。
The immunoproteasome (i-20S) has emerged as a therapeutic target for autoimmune and inflammatory disorders and hematological malignancies. Inhibition of the chymotryptic β5i subunit of i-20S inhibits T cell activation, B cell proliferation and dendritic cell differentiation in vitro and suppresses immune responses in animal models of autoimmune disorders and allograft rejection. However, cytotoxicity to immune cells has accompanied the use of covalently reactive β5i inhibitors, whose activity against the constitutive proteasome (c-20S) is cumulative with time of exposure. Herein we report a structure-activity relationship study of a class of noncovalent proteasome inhibitors with picomolar potencies and thousands-fold selectivity for i-20S over c-20S. Furthermore, these inhibitors are specific for β5i over the other 5 active subunits of i-20S and c-20S, providing useful tools to study functions of β5i in immune responses. The potency of these compounds in inhibiting human T cell activation suggests that they may have therapeutic potential.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
影响因子：
7.8
作者：
Kisselev AF;Groettrup M
通讯作者：
Groettrup M
影响因子：
82.9
作者：
Muchamuel, Tony;Basler, Michael;Groettrup, Marcus
通讯作者：
Groettrup, Marcus
影响因子：
3.2
作者：
Cui, Haissi;Baur, Regina;Groll, Michael
通讯作者：
Groll, Michael
影响因子：
--
作者：
Ichikawa HT;Conley T;Muchamuel T;Jiang J;Lee S;Owen T;Barnard J;Nevarez S;Goldman BI;Kirk CJ;Looney RJ;Anolik JH
通讯作者：
Anolik JH