Development of a selective S1P1 receptor agonist, Syl930, as a potential therapeutic agent for autoimmune encephalitis.
Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from secondary lymphoid organs and is a validated drug target for the treatment of autoimmune disorders. However, during the preclinical and clinical trials of S1P1 modulators, the undesired activation of S1P3, a subtype of sphingosine 1-phosphate (S1P) receptors family, by S1P1 modulators often results in bradycardia in patients. Thus, we designed and synthesized a new series of selective S1P1 agonists. One of them, Syl930 (the prodrug), is preference to activate S1P1 but not S1P3. In this study, we further investigated the therapeutic potential of Syl930 on an experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. We found that Syl930 can activate and internalize S1P1 receptors and effectively decreased the periphery blood lymphocytes (PBL) in SD rats, and subsequently rendered PBL insensitive to egress signal from secondary lymphoid organs (SLO). Intriguingly, the treatment of Syl930 did not bring any side effect on heart rate of the tested rats. Furthermore, the suppressed PBL caused by Syl930 was able to recover within 3 days after the last dose of treatment, which is correlated to the relatively short elimination half-life of Syl930. In the rat EAE model, therapeutic treatment with Syl930 significantly inhibited the progression of EAE and EAE-associated histological changes in brain and spinal cord of Lewis rats. These results illustrate that, as a selective S1P1 agonist, Syl930 exhibits a profound and rapidly reversible suppression of lymphocyte trafficking and it has the potential to serve as a therapeutic agent for autoimmune encephalitis.
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Jing
J
Jin
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Jinping
J
Hu
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Wanqi
W
Zhou
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Xiaojian
X
Wang
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Qiong
Q
Xiao
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Nina
N
Xue
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: yindali@imm.ac.cn.
Dali
D
Yin
State Key laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
Xiaoguang
X
Chen
D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003711:Demyelinating Diseases / Q000517:prevention & control; D004660:Encephalitis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D050031:Hashimoto Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011412:Propanolamines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D007166:Immunosuppressive Agents; D010080:Oxazoles; D011412:Propanolamines; D049349:Receptors, Lysosphingolipid; C000590835:Syl930
Autoimmune encephalomyelitis; Lymphocyte; Multiple sclerosis; S1P(1); S1P(1) agonist; Syl930