Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions.
Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions.
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DOI：
10.1124/mol.108.049783
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发表时间：
2008-11
影响因子：
3.6
通讯作者：
Rosen H
中科院分区：
文献类型：
--
作者：
Gonzalez-Cabrera PJ;Jo E;Sanna MG;Brown S;Leaf N;Marsolais D;Schaeffer MT;Chapman J;Cameron M;Guerrero M;Roberts E;Rosen H
有强有力的证据表明，磷酸鞘氨苷（S1P）中的两性离子磷酸盐和胺基与S1P受体跨膜3 （TM3）细胞外表面的保守R和E残基相互作用。R120和E121对高亲和力配体-受体相互作用的贡献是必不可少的，因为单点R120A或E121A S1P1突变体既不结合S1P也不转导S1P的功能。由于S1P受体具有治疗意义，因此确定具有不同结合模式和体内疗效的强效选择性激动剂具有重要的药理学意义。在这里，我们描述了一种适度水溶性的高选择性S1P1激动剂（CYM-5442），它不需要R120或E121残基来激活S1P1依赖的p42/p44 MAPK磷酸化，这在S1P1中定义了一个新的疏水口袋。CYM-5442是体外S1P1内化、磷酸化和泛素化的完全激动剂。重要的是，CYM-5442是一种诱导和维持s1p1依赖性淋巴细胞减少的完全激动剂，可减少65%的b淋巴细胞和85%的t淋巴细胞。CYM-5442淋巴细胞减少的诱导是剂量和时间依赖性的，需要血清浓度在50 nM范围内。体外测量的CYM-5442对S1P1的激活被一种特异性S1P1拮抗剂（W146）非竞争性抑制，该拮抗剂对S1P、FTY720-P和SEW2871具有竞争性。此外，给药W146或药代动力学激动剂清除后，CYM-5442引起的淋巴细胞减少可以逆转。小鼠药代动力学也表明CYM-5442在中枢神经组织中有明显的分裂。这些数据表明，CYM-5442在体外激活s1p1依赖途径，并通过一个疏水口袋在体内达到完全有效的水平，该口袋与S1P结合的正位位点分离，是头群依赖的。
Strong evidence exists for interactions of zwitterionic phosphate and amine groups in Sphingosine-1 phosphate (S1P) to conserved R and E residues present at the extracellular face of transmembrane-3 (TM3) of S1P receptors. The contribution of R120 and E121 for high affinity ligand-receptor interactions is essential, as single-point R120A or E121A S1P1 mutants neither bind S1P nor transduce S1P function. Because S1P receptors are therapeutically interesting, identifying potent selective agonists with different binding modes and in vivo efficacy is of pharmacological importance. Here we describe a modestly water-soluble highly-selective S1P1 agonist (CYM-5442) that does not require R120 or E121 residues for activating S1P1-dependent p42/p44 MAPK phosphorylation, which defines a new hydrophobic pocket in S1P1. CYM-5442 is a full agonist in vitro for S1P1 internalization, phosphorylation and ubiquitination. Importantly, CYM-5442 was a full agonist for induction and maintenance of S1P1-dependent lymphopenia, decreasing B-lymphocytes by 65% and T-lymphocytes by 85% of vehicle. Induction of CYM-5442 lymphopenia was dose and time-dependent, requiring serum concentrations in the 50 nM range. In vitro measures of S1P1 activation by CYM-5442 were non-competitively inhibited by a specific S1P1 antagonist (W146), competitive for S1P, FTY720-P and SEW2871. In addition, lymphopenia by CYM-5442 was reversed by W146 administration or upon pharmacokinetic agonist clearance. Pharmacokinetics in mice also indicated that CYM-5442 partitions significantly in central nervous tissue. These data show that CYM-5442 activates S1P1-dependent pathways in vitro and to levels of full efficacy in vivo through a hydrophobic pocket, separable from the orthosteric site of S1P binding that is headgroup dependent.
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DOI：
10.1073/pnas.1832725100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Rosen, H;Alfonso, C;McHeyzer-Williams, MG
通讯作者：
McHeyzer-Williams, MG
影响因子：
4.8
作者：
Sanchez, T;Estrada-Hernandez, T;Hla, T
通讯作者：
Hla, T
影响因子：
14.8
作者：
Sanna, M. Germana;Wang, Sheng-Kai;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
4.8
作者：
Fujiwara, Yuko;Osborne, Daniel A.;Tigyi, Gabor
通讯作者：
Tigyi, Gabor
影响因子：
4.8
作者：
Oo, Myat Lin;Thangada, Shobha;Hla, Timothy
通讯作者：
Hla, Timothy