CN115607550A - 一种tlr7/8激动剂在抑制hiv中的应用 - Google Patents
一种tlr7/8激动剂在抑制hiv中的应用 Download PDFInfo
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- CN115607550A CN115607550A CN202110797018.9A CN202110797018A CN115607550A CN 115607550 A CN115607550 A CN 115607550A CN 202110797018 A CN202110797018 A CN 202110797018A CN 115607550 A CN115607550 A CN 115607550A
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Abstract
本发明公开了一种TLR7/8激动剂在抑制HIV中的应用。发明人通过大量试验发现某些TLR7/8双激动剂化合物具有显著激活HIV潜伏感染细胞的作用，可刺激机体产生抗病毒细胞因子，杀伤被激活的潜伏感染细胞，从而加速潜伏病毒的清除，有望用作抗HIV药物，为艾滋病的彻底治愈提供一种新途径。
Description
技术领域
本发明涉及化学医药技术领域，具体涉及一种TLR7/8激动剂在抑制HIV中的应用。
背景技术
在过去的40年中，由HIV-1引起的获得性免疫缺陷综合征(AIDS，也称为艾滋病)已成为世界上最具传染性和致命性的传染病之一。尽管高效抗逆转录病毒疗法(HAART)可以有效抑制HIV-1的复制和传播，但感染HIV的患者仍无法治愈，需要终生治疗。治愈艾滋病毒的主要障碍是即使在接受ART治疗的艾滋病毒患者中，潜伏病毒库也会持续存在。潜伏库包含有复制能力的HIV DNA前病毒，在ART处理下其转录沉默。这些潜伏细胞不转录或很低转录HIV RNA并表达相关蛋白，并且没有针对性的特定细胞表面潜伏期标记。因此可以逃避宿主免疫系统和抗逆转录病毒药物的识别和消除。目前HIV治愈策略中研究最多的是利用小分子首先激活潜伏病毒库，然后利用宿主免疫细胞杀伤激活的HIV感染细胞。
Toll样受体是与先天免疫系统有关的模式识别受体(PRR)家族，可感知病原体相关的分子模式并防御早期感染。在人类中共有10种功能性TLR，其中TLR3、TLR7、TLR8和TLR9位于内体的膜表面，主要负责病毒和细胞内细菌的检测。TLR7和TLR8具有相似的二聚体结构，并且都识别单链RNA(ssRNA)。TLR7和TLR8的分布和功能不同。TLR7主要分布在浆细胞样树突状细胞(pDCs)和B细胞中，而TLR8主要分布在单核细胞，巨噬细胞和髓样树突状细胞(mDCs)中。TLR7和TLR8的激活均募集MyD88，但TLR8激活下游信号转录NF-κB诱导促炎细胞因子，而TLR7主要激活IRF7诱导抗病毒1型干扰素。由于TLR7/8激动剂可以特异性激活免疫细胞和抗病毒调节，因此从理论上讲它们可以成为更有效的艾滋病潜伏病毒库激动剂。
几种TLR7/8激动剂已被表征为在体外和体内可以激活HIV潜伏病毒库。GS9620是由吉利德科学公司合成的强效TLR7特异性激动剂。研究表明，GS9620可以诱导接受抗逆转录病毒(ART)治疗的，来自感染HIV的患者的PBMC中HIV RNA的逆转。GS9620还增强了HIV免疫效应细胞的活化，从而清除HIV感染的细胞。并且GS9620可在ART上诱导短暂病毒血症，并减少SIV感染的猕猴的潜伏储藏。然而，研究者没有在猕猴中复制先前的结果。证明GS9620与HIV广谱中和抗体PGT121结合在ART被中断时可延迟SHIV感染猴子的病毒反弹。已显示TLR7/8激动剂R848可以诱导HIV潜伏细胞U1和OM-10.1中p24的表达。TLR8激动剂3M-002可以激活与单核细胞来源的树突状细胞共培养的CD4 T细胞系J-Lat。TNF-α间接介导细胞的作用，和protratin的联合作用可增加HIV潜伏病毒库的重新激活。目前研究已经表明TLR8激动剂而不是TLR7激动剂可以促进CD4 T细胞表达IL-6和CD69激活表面标志物的增加。TLR8参与可能会诱导HIV复制并逆转潜伏病毒库。
发明内容
本发明提供一种化合物在制备抗人类免疫缺陷病毒(HIV，也称为艾滋病病毒)的药物中的应用。
具体地，该化合物选自如下结构：
其中，
R1选自：H、卤素、氨基亚甲基、(取代氨基)亚甲基或其季铵盐、杂环基取代的亚甲基、叠氮亚甲基、膦酸基亚甲基、膦酸二乙酯基亚甲基、C1-C6烷基、C1-C6烷氧基、-CF3、-COOH、-COOCH3、-CN、-CH2OH；
R2为-XR6，其中X代表NH、S、O，R6选自：C1-C6烷基、C1-C3烷氧基取代的C1-C3烷基；
R2'选自：H、C1-C6烷基；
R3选自：H、C1-C6烷基；
R4代表环上一个或多个独立的取代基，选自：H、卤素、C1-C6烷基、C1-C6烷氧基；
R5选自：H、C1-C6烷基。
具体地，杂环基为
具体地，(取代氨基)亚甲基为(烷基取代氨基)亚甲基，例如
具体地，R1选自：
在本发明的一个实施方式中，R2为-NHR6。
具体地，R6为正丁基或甲氧基乙基。
具体地，R2为
具体地，R2'为C1-C6烷基；在本发明的一个实施例中，R2'为正戊基。
具体地，R3为H或甲基。
具体地，R4为H或甲氧基。
具体地，R5为H或甲基。
在本发明的一个实施方式中，化合物具有如下结构：
其中R1、R2、R4具有本发明上述相应定义。
更具体地，化合物具有如下结构：
其中R4具有本发明上述相应定义。
在本发明另一个实施方式中，化合物具有如下结构：
其中R1、R2'、R5具有本发明上述相应定义。
更具体地，化合物具有如下结构：
其中R1具有本发明上述相应定义。
在本发明另一个实施方式中，化合物具有如下结构：
其中，R1、R2'具有本发明上述相应定义。
更具体地，化合物具有如下结构：
在本发明的实施例中，化合物选自如下结构：
具体地，抗HIV包括抗HIV潜伏、促进杀伤HIV感染细胞。
具体地，抗HIV潜伏包括激活HIV潜伏感染细胞。
具体地，该HIV潜伏感染细胞可以为单核细胞、T细胞(如CD4+T细胞、CD8+T细胞)、NK细胞、巨噬细胞、肥大细胞、树突状细胞等。
本发明还提供一种化合物在制备增强抗HIV效果的药物中的应用。
本发明还提供一种化合物在制备预防HIV反弹的药物中的应用。
本发明还提供一种化合物在制备预防、治疗HIV感染引起的疾病、延迟HIV感染引起的疾病发病的药物中的应用。
具体地，该疾病为AIDS及其并发症、艾滋病相关综合征(AIDS-related complex，ARC)(又称为副艾滋病或艾滋病前期)。
具体地，该疾病的受试者为哺乳动物，特别是人类。
具体地，在上述应用中，HIV为1型人类免疫缺陷病毒(HIV-1)。
具体地，在上述应用中，该化合物可以可单独使用，也可与其它药物和/或治疗方法联合使用。
具体地，其他药物可以选自：核苷类逆转录酶抑制剂、非核苷类逆转录酶抑制剂(NNRTI)或蛋白酶抑制剂；其中，核苷类逆转录酶抑制剂可以选自：齐多夫定zidovudine(AZT或ZDV)；地丹诺辛didanosine(ddl、Videx)；扎西他滨Zalcitabine(ddc)；司他夫定Stavudine(d4T)；拉米夫定Lamivudine(3TC)；阿巴卡韦abacavir(1592U89Ziagen)；非核苷类逆转录酶抑制剂(NNRTI)可以选自：奈韦拉平nevirapine；地拉韦啶delavird；依非韦伦efavirene；蛋白酶抑制剂可以选自：沙奎那韦saguinavir；茚地那韦indinavir；利托那韦ritonavir；奈非那韦nelfinavirr；安普那韦amprenavir。
具体地，在上述应用中，药物还含有一种或多种药学上可接受的辅料。
具体地，在上述应用中，药物可以采用任意的剂型或给药形式，特别是口服剂型，本领域技术人员可以根据情况选用，包括，但不限于，片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、液体、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如，口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如，皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如，直肠栓剂、阴道栓剂)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等。
本发明的发明人通过大量试验发现某些TLR7/8双激动剂化合物具有显著激活HIV潜伏感染细胞的作用，可刺激机体产生抗病毒细胞因子，杀伤被激活的潜伏感染细胞，从而加速潜伏病毒的清除，有望用作抗HIV药物，为艾滋病的彻底治愈提供一种新途径。
附图说明
图1所示为各激动剂激活U1细胞的检测结果。
图2所示为各激动剂激活J-LAT 6.3细胞的检测结果。
图3所示为各激动剂体外激活感染者的细胞因子的检测结果。
图4所示为各激动剂在体外激活感染者PBMC病毒库能力的检测结果。
图5所示为各激动剂体外激活T细胞的能力的检测结果。
图6所示为各激动剂体外激活NK细胞的能力的检测结果。
图7所示为各激动剂体外激活原代NK细胞杀伤HIV感染细胞系的检测结果。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
术语“烷基”指的是直链或支链的且不含不饱和键的烃基，且该烃基以单键与分子其它部分连接。典型的烷基基团含有1至6(例如1、2、3、4、5、6)个碳原子，如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基等。
术语“烷氧基”是指羟基中的氢被烷基取代后形成的取代基，C1-C6的烷氧基指含有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、丁氧基等。
术语“卤素”是指溴、氯、碘或氟。
术语“TLR”指Toll like receptor，即Toll样受体。
本文所引用的各种出版物、专利和公开的专利说明书，其公开内容通过引用整体并入本文。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
制备实施例：
实施例1：化合物D1
参照专利文献CN108069963A中化合物N01的制备方法，制备化合物D1。
实施例2：化合物D2
参照专利文献CN108069963A中化合物N10的制备方法，制备化合物D2。
实施例3：化合物D3
参照专利文献CN108069963A中化合物N35的制备方法，制备化合物D3-1,参照专利文献CN108069963A中由化合物N29制备N01的流程以D3-1为原料制备D3(合成路线如下所示)。化合物D3的结构鉴定数据如下：1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.6Hz,1H),7.40(t,J＝5.8Hz,1H),7.29(d,J＝8.6Hz,1H),7.26(d,J＝7.9Hz,2H),7.21(d,J＝7.9Hz,2H),5.06(s,2H),4.17(s,2H),3.79(td,J＝13.2,5.4Hz,2H),3.65(t,J＝5.4Hz,2H),3.44(s,3H),3.42(s,2H),2.25(s,6H).13C NMR(100MHz,CDCl3)δ160.3,159.7,155.1,144.0,138.2,136.6,132.6,129.5,129.0,128.0,127.9,71.0,63.9,59.0,45.2,44.0,40.2.HRMS(ESI)calcd for C20H27N6O[M+H]+367.2246,found 367.2239.
实施例4：化合物D4
参照专利文献CN108069963A中化合物N11的制备方法，制备化合物D4。
实施例5：化合物D5
参照专利文献CN108069963A中化合物N35的制备方法，制备化合物D5-1,参照专利文献CN108069963A中由N29制备N01的流程以D5-1为原料制备D5(合成路线如下所示)。化合物D5的结构鉴定数据如下：1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.6Hz,1H),7.28(d,J＝8.6Hz,1H),7.07(m,2H),6.89(s,1H),6.81(dd,J＝7.6,1.5Hz,1H),4.90(s,2H),4.16(s,2H),3.82(s,3H),3.55(dt,J＝7.2,5.9Hz,2H),3.40(s,2H),2.25(s,6H),1.74–1.64(m,2H),1.46(dq,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ160.3,160.0,157.4,155.0,144.3,134.0,132.7,130.3,128.0,127.8,126.6,121.2,111.1,64.5,55.5,45.5,40.2,38.2,31.5,20.2,13.9.HRMS(ESI)calcd for C22 H31N6O[M+H]+395.2559,found 395.2556.
实施例6：化合物S1
参照专利申请CN202011644306.2中描述的化合物N4的制备方法，制备化合物S1(合成路线如下所示)。化合物S1的结构鉴定数据如下：1H NMR(400MHz,Chloroform-d)δ7.21(d,J＝7.8Hz,2H),7.06(d,J＝7.8Hz,2H),7.01(s,1H),4.41(s,2H),3.84(s,2H),3.82(s,2H),2.37(t,J＝7.6Hz,2H),2.28(s,3H),2.05(s,2H),1.57(m,2H),1.32(m,4H),0.90(t,J＝6.8Hz,3H).13C NMR(101MHz,Chloroform-d)δ154.4,151.9，140.9，139.3,139.1，128.6，127.2，124.0，118.6，46.1，37.5，31.7，30.5，27.8，22.5，21.4，14.0.HRMS(ESI)calcd for:C19H28N3[M+H]+298.2283,found 298.2283.
实施例7：化合物S2
参照实施例6化合物S1的合成方法，将最后一步的反应原料二甲胺替换为四氢吡咯，得到化合物S2。化合物S2的结构鉴定数据如下：1H NMR(400MHz,Chloroform-d)δ7.25(d,J＝7.7Hz,2H),7.06(d,J＝7.7Hz,2H),7.02(s,1H),4.30(s,2H),3.86(s,2H),3.60(s,2H),2.51(m,4H),2.39(t,J＝7.8Hz,2H),2.31(s,3H),1.80(m 4H),1.60(t,J＝7.6Hz,2H),1.35(m,4H),0.94–0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,Chloroform-d)δ154.37，152.2,139.16，139.08，136.99，129.00，128.30，124.19，118.36，60.41，54.17，37.57，31.69，30.55，27.81，23.42，22.51，21.59，14.05.HRMS(ESI)calcd for:C23H34N3[M+H]+352.2753,found 352.2742.
实施例8：化合物S3
参照专利申请CN202011644306.2中描述的化合物N1的制备方法，制备化合物S3，(合成路线如下所示)。化合物S3的结构鉴定数据如下：1HNMR(400MHz,Chloroform-d)δ7.95(d,J＝8.6Hz,1H),7.84(d,J＝8.6Hz,1H),7.27(m,4H),5.00(s,2H),4.29(s,2H),3.47(s,2H),2.61(t,J＝7.7Hz,2H),2.29(s,6H),1.80(p,J＝7.4Hz,2H),1.44(tq,J＝13.7,7.8,6.0Hz,4H),0.95(t,J＝6.8Hz,3H).13C NMR(101MHz,Chloroform-d)δ157.27，156.02，140.58,140.25，138.64，135.99，133.56，129.54，129.10，127.41，124.01，63.77，45.04，44.63，31.57，31.07，27.18，22.54，13.98.m/z:[M+H]+363.4.
实施例9：化合物S4
参照专利文献CN108069963A中化合物N35的制备方法，制备化合物S4-1,参照专利文献CN108069963A中由N29制备N01的流程以S4-1为原料制备S4(合成路线如下所示)。化合物S4的结构鉴定数据如下：1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝8.6Hz,1H),7.29(d,J＝8.6Hz,1H),7.26–7.21(m,4H),7.10(t,J＝6.0Hz,1H),4.97(s,2H),4.32(q,J＝7.2Hz,1H),3.60(q,J＝6.8Hz,2H),3.40(s,2H),2.24(s,6H),1.73(m,5H),1.50(dt,J＝14.9,7.4Hz,2H),1.02(t,J＝7.4Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.39,160.24,158.58,144.54,143.74,136.99,132.86,129.21,127.56,127.67,127.22,64.04,46.65,45.39,40.22,31.53,20.79,20.22,13.89.
试验实施例：
实施例1：激动剂TLR7/8活性检测
试剂：HEK-blue hTLR7，HEK-blue hTLR8细胞；DMEM完全培养基：DMEM，10％FBS，1％PS，50μg/ml Normocin,30μg/ml blasticidin，100μg/ml Zeocin；HEK-blueDetection。
将1×107冻存的细胞从液氮迅速放入37℃水浴，完全融化后转移至2ml提前预热的DMEM培养基中，800rpm离心5min，弃上清。用10ml DMEM完全培养基重悬后转入10cm培养皿中，放置于37℃5％CO2培养箱培养，隔天1：3传代。
加入20μl不同起始浓度的激动剂(如表1所示，其中R848、VTX-2337、GS-9620作为阳性对照)或阴性对照PBS至96孔板中，2倍比稀释10个梯度。将HEK-blue hTLR7/8细胞用5ml PBS冲洗使细胞掉落，计数后用HEK-blue detection重悬细胞至4×105/ml浓度，每孔加入180μl细胞，将96孔板放入37℃5％CO2培养箱培养12～16小时，然后在630nm检测SEAP读数。
半最大效应浓度(EC50)为能够引发50％最大效应的分子浓度，EC50的浓度越小说明药效越好。如表1所示，R848的hTLR7 EC50＝399.6nM，hTLR8 EC50＝1062nM，本发明中TLR7/8双激动剂D1的hTLR7 EC50＝40.2nM，hTLR8 EC50＝6.5nM，TLR7/8双激动剂D5的hTLR7 EC50＝20nM，hTLR8 EC50＝44.1nM。VTX2337的hTLR7 EC50>10000nM，hTLR8 EC50＝150.8nM，本发明的TLR8特异激动剂S1的hTLR7 EC50>10000nM，hTLR8 EC50＝55.2nM。
表1试验化合物及EC50结果
实施例2：激动剂激活HIV潜伏感染细胞系活性检测
激动剂激活U1细胞检测：加入不同浓度的激动剂或阳性对照TNF-α或阴性对照DMSO至96孔板中，2倍比稀释8个梯度。将U1细胞800rpm离心5min，用1640培养基重悬细胞至1×106/ml浓度，每孔加入100μl细胞，将96孔板放入37℃5％CO2培养箱培养。24h后将细胞离心，收集细胞上清利用p24 ELISA检测试剂盒测定p24浓度以测定激动剂激活U1细胞产生HIV病毒颗粒的活性。
实验结果：如图1A所示，发明人检测了9种新型激动剂和3种商业化激动剂在2μM和500nM的浓度下对于U1细胞的激活，发现TLR7/8双激动剂和TLR8特异激动剂可以强烈的激活U1细胞产生HIV病毒颗粒，但是TLR7特异性激动剂相对于DMSO组未显示出明显的激活。其中D1、D5和S1分别在各自的组别中展现出很强的激活能力。发明人选择了这三个激动剂与R848、VTX-2337以及GS9620按照2倍比稀释，8个稀释度来刺激U1细胞，如图1B所示，D1展现出最强的激动活性，EC50＝70nM。但是GS9620在16μM的浓度下都无法激活U1细胞释放HIV病毒颗粒。
激动剂激活J-LAT 6.3细胞检测：招募健康志愿者采集外周血，利用蔗糖密度梯度离心分离得到外周单个核细胞(PBMC)。用1640培养基重悬PBMC至3～4×106/ml浓度，每孔加入100μl细胞至96孔板中，再依次加入不同浓度的激动剂或阴性对照DMSO，将96孔板放入37℃5％CO2培养箱培养。24h后将细胞4000rpm离心5min，收集细胞上清。
将J-LAT 6.3细胞用1640培养基重悬细胞至1×106/ml浓度，每孔加入100μl细胞，再加入收集的PBMC上清加入至相应孔中，将96孔板放入37℃5％CO2培养箱培养。48h后将细胞离心收集，利用BD LSRFortessa分析仪检测J-LAT 6.3GFP阳性率。J-LAT 6.3细胞内含有LTR驱动的GFP基因，如果J-LAT 6.3细胞潜伏病毒激活转录，就会呈现GFP阳性。
如图2A所示，发明人检测了D1、D5、S1、R848、VTX-2337和GS9620在1μM的浓度下间接激活J-LAT 6.3细胞，发现TLR7/8双激动剂和TLR8特异激动剂可以强烈的激活J-LAT 6.3细胞的HIV转录表达，但是TLR7特异性激动剂相对于DMSO组未显示出明显的激活。其中D1和D4的效果最强，均能够刺激10％左右的J-LAT 6.3细胞激活HIV的转录表达。接下来发明人检测了不同浓度的激动剂对于J-LAT的间接激活，如图2B所示，发现D1和D4在100nM以下可以激活J-LAT细胞，S1激动活性稍弱，在1μM浓度下能够强烈激活J-LAT细胞，但是TLR7特异性激动剂GS9620在16μM的最高浓度下也无法激活J-LAT 6.3。
实施例3：激动剂体外激活艾滋慢性感染者的细胞因子和HIV病毒检测
采集了接受高效抗逆转录病毒疗法2年以上，体内病毒载量小于50拷贝/ml的艾滋慢性感染者的外周血，利用蔗糖密度梯度离心分离得到PBMC。用1640培养基重悬6个慢性感染者和2个健康志愿者的PBMC至4×106/ml浓度，加入500μl细胞至24孔板中，用1μM的D1、D5、S1、R848、VTX-2337、GS9620以及阳性对照PMA+Inomycin，阴性对照DMSO刺激，37℃培养。48h后收集上清利用Legendplex多因子检测试剂盒检测TNF-α、IFN-α、IFN-γ、IL-1β、IL-18和IL-23。96h后收集上清提取RNA，反转录成cDNA，利用病毒载量检测试剂盒RT-PCR检测上清中的病毒载量。
结果如图3所示，上清检测了6种细胞因子，发现TLR7/8激动剂的D1、D5能够强烈的刺激PBMC分泌这6种细胞因子，TLR8激动剂S1、VTX-2337能够刺激高浓度的TNF-α、IFN-γ、IL-1β、IL-18和IL-23，但是基本不诱导分泌IFN-α。TLR7/8激动剂R848和TLR7激动剂GS9620的对于炎症因子的激活活性较弱，但是刺激IFN-α的能力较强。总体来说，D1、D5和S1三个小分子能够较强地刺激人源PBMC产生炎症及抗病毒细胞因子。
随后检测了激动剂在体外激活感染者PBMC病毒库能力，结果如图4所示。图4显示阳性对照PMA+Inomycin能够强烈激活病人的潜伏病毒库分泌HIV至细胞上清中，D1、D5以及S1是激活能力最强的三个激动剂，相较于商业化的分子有着更强的激活潜伏病毒库能力。
实施例4：激动剂体外激活T细胞以及NK细胞的能力
招募健康志愿者采集外周血，分离得到PBMC。用1μM的D1、D5、S1、R848、VTX-2337、GS9620以及阴性对照DMSO刺激24h，2000rpm离心10min收集细胞，利用PE-Cy7-抗CD3抗体、PE-抗CD4抗体、FITC-抗CD8抗体、标记CD4和CD8 T细胞，BV421-抗CD25抗体、BV510-抗CD69抗体检测T细胞激活。利用PE-抗CD16抗体、APC-抗CD56抗体，标记CD16 bright和CD16 dimNK细胞，BV421-抗NKG2D抗体，BV510-抗CD69抗体检测NK细胞激活，抗体4℃孵育20min后，利用BD LSRFortessa分析仪上机检测。
结果如图5所示，CD4 T细胞能够被所有六种激动剂激活，其中TLR7/8双特异型激动剂D1和D5激活CD69和CD25的能力明显强于TLR7或者TLR8特异性激动剂，D1与DMSO相比较的统计学差异p值小于0.0005。但是激动剂激活CD8 T细胞的功能明显弱于激活CD4 T细胞，仅D1能够较明显地激活CD8 T细胞的CD25和CD69。TLR7/8激动剂可以强烈地激活CD56bright和CD56dim NK细胞，上调CD69激活标志的表达。NKG2D是NK细胞应对感染的一个重要激活标志物，D1同样可以很强地激活CD56bright和CD56dim NK细胞的NKG2D表达。
利用NK磁珠(Miltenyi)阴选分离PBMC得到NK细胞，直接用1μM的D1、D5、S1、R848、VTX-2337、GS9620以及阴性对照DMSO刺激24h，离心收取上清利用ELISA试剂盒检测IFN-γ浓度。用于流式检测的NK细胞提前6h加入Golgi-stop，离心收取细胞利用PE-抗CD16抗体，APC-抗CD56抗体，APC-Cy7-抗CD69抗体染色20min，随即利用BD固定破膜液4℃孵育20min，FITC-抗IFN-γ抗体染色40min，利用BD LSRFortessa分析仪上机检测。
实验结果：如图6所示，通过检测刺激24h后的PBMC上清IFN-γ，以及NK细胞的激活标志物CD69和细胞内IFN-γ表达，发明人发现TLR7/8激动剂能够直接刺激NK细胞激活上调CD69的表达并且分泌IFN-γ。其中TLR7/8双特异激动剂D1和D5的激活能力最强，其次为TLR8特异性激动剂S1和VTX2337以及TLR7/8双激动剂R848，TLR7特异性激动剂GS9620激活能力最弱。表明小分子D1、D5和S1能够强烈地诱导NK的激活并且分泌抗病毒细胞因子IFN-γ。
实施例5：激动剂体外激活原代NK细胞杀伤HIV感染细胞系
传代HEK 293T细胞在15cm培养皿中至70％汇合度，pNL4-3质粒利用PEI进行转染，转染14～16h后换DMEM完全培养基放入培养基培养48h，然后4000rpm 4℃离心10min收集上清液，冻存至-80℃。将CEM.NKR CCR5+Luc+细胞计数加入pNL4-3 400×g室温离心1h感染，随即放入37℃培养箱中培养过夜，更换10％FBS的1640培养基继续培养48h。将健康志愿者的外周血分离得到PBMC，然后利用美天旎NK磁珠阴选得NK细胞。加入1μM的D1、S1、GS9620和DMSO刺激，放入培养箱培养24h。
将HIV广谱中和抗体3BNC117调整至首孔5μg/ml，在96孔板中进行3倍比稀释4个稀释度2个重复，同时设置未感染细胞组(CC)和感染细胞未加抗体组(VC)。每孔加入2×104个pNL4-3感染的CEM.NKR细胞与抗体37℃共孵育30min。再按照效应细胞：靶细胞＝6：1的比例加入刺激后的NK细胞。用于Luciferase荧光检测的细胞直接放入培养箱37℃共孵育6h，离心收集的细胞利用Luciferase检测试剂盒检测RLU读值，计算得到ADCC杀伤百分比，上清利用ELISA检测IFN-γ和Granzyme B的表达。用于流式检测的细胞加入APC-Cy7抗CD107a抗体和Golgi-stop，放入培养箱37℃共孵育4h。然后离心细胞利用CD3、CD16、CD56和IFN-γ进行胞内染色，BD LSRFortessa分析仪流式检测CD107a和IFN-γ表达。
结果如图7所示，随着3BNC117抗体浓度的增加，NK细胞杀伤pNL4-3感染的CEM.NKR比例也随之增加，D1、S1和GS9620均可以增加NK细胞ADCC杀伤能力，但TLR7/8双激动剂的D1激活NK的ADCC能力最强，其次为TLR8特异性激动剂S1和TLR7特异性激动剂GS9620。CD107a是表征NK细胞脱粒杀伤靶细胞的功能性标志物，流式分析的结果显示，NK细胞能够被D1和S1强烈地激活，增加CD107a的表达和IFN-γ的分泌，GS9620的激活能力相较于D1和S1都较弱。并且发明人检测了ADCC孵育后上清IFN-γ和Granzyme B的表达，同样D1和S1都能够增加NK细胞ADCC作用中IFN-γ和Granzyme B的分泌。实验结果显示出激动剂D1和S1能够强烈地激活NK细胞，增加其ADCC杀伤HIV感染细胞的活性，上调CD107a表达增加脱粒能力，增加IFN-γ和Granzyme B的分泌。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
Claims (10)
1.一种化合物在制备抗HIV、预防和/或治疗HIV感染引起的疾病或延迟HIV感染引起的疾病发病的药物中的应用，其中所述化合物选自如下结构：
其中，
R1选自：H、卤素、氨基亚甲基、(取代氨基)亚甲基或其季铵盐、杂环基取代的亚甲基、叠氮亚甲基、膦酸基亚甲基、膦酸二乙酯基亚甲基、C1-C6烷基、C1-C6烷氧基、-CF3、-COOH、-COOCH3、-CN、-CH2OH；
R2为-XR6，其中X代表NH、S、O，R6选自：C1-C6烷基、C1-C3烷氧基取代的C1-C3烷基；
R2'选自：H、C1-C6烷基；
R3选自：H、C1-C6烷基；
R4代表环上一个或多个独立的取代基，选自：H、卤素、C1-C6烷基、C1-C6烷氧基；
R5选自：H、C1-C6烷基。
2.如权利要求1所述的应用，其特征在于，R1选自：
3.如权利要求1所述的应用，其特征在于，R2为
4.如权利要求1所述的应用，其特征在于，R2'为正戊基。
5.如权利要求1所述的应用，其特征在于，R3为H或甲基。
6.如权利要求1所述的应用，其特征在于，R4为H或甲氧基。
7.如权利要求1所述的应用，其特征在于，R5为H或甲基。
8.如权利要求1所述的应用，其特征在于，所述化合物选自：
9.如权利要求1-8任一项所述的应用，其特征在于，所述抗HIV包括抗HIV潜伏、促进杀伤HIV感染细胞；
优选地，所述抗HIV潜伏包括激活HIV潜伏感染细胞；
优选地，所述HIV潜伏感染细胞选自：单核细胞、T细胞、NK细胞、巨噬细胞、肥大细胞、树突状细胞。
10.如权利要求1-8任一项所述的应用，其特征在于，所述疾病为AIDS或其并发症、艾滋病相关综合征。
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| CN114685491A (zh) * | 2020-12-31 | 2022-07-01 | 清华大学 | 吡啶-2-胺衍生物及其药物组合物和用途 |
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| CN108069963A (zh) * | 2017-11-17 | 2018-05-25 | 清华大学 | 吡啶并嘧啶衍生物或其盐及其制法、药物组合物和用途 |
| CN114685491A (zh) * | 2020-12-31 | 2022-07-01 | 清华大学 | 吡啶-2-胺衍生物及其药物组合物和用途 |
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