CN115942970A - N-酰基氨基酸产物及用途 - Google Patents
N-酰基氨基酸产物及用途 Download PDFInfo
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- CN115942970A CN115942970A CN202180050291.3A CN202180050291A CN115942970A CN 115942970 A CN115942970 A CN 115942970A CN 202180050291 A CN202180050291 A CN 202180050291A CN 115942970 A CN115942970 A CN 115942970A
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- leucine
- glycine
- oleoyl
- amino acid
- fatty acid
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Abstract
本发明涉及N‑酰基氨基酸产物及其在诊断和治疗疾病中的用途。
Description
序列表的引入作为参考
作为公开内容的单独部分,本申请含有计算机可读形式的序列表(文件名55769A_Seqlisting.text;2,597字节-ASCII文本文件,创建于2021年8月17日),其整体引入本文作为参考。
发明领域
本发明涉及N-酰基氨基酸产物及其在诊断和治疗疾病中的用途。
背景技术
由动脉粥样硬化引起的心血管疾病(CVD)是全世界死亡的主要原因。最常见的慢性肝病非酒精性脂肪肝病(NAFLD)先于和/或促进动脉粥样硬化的发展。一部分NAFLD患者发展为更严重的非酒精性脂肪性肝炎(NASH)和肝纤维化,其可进一步加速动脉粥样硬化进展和CVD事件。实际上,CVD是NAFLD患者死亡的主要原因,特别是患有NASH的那些。
本领域仍然需要用于诊断和治疗NASH、纤维化和CVD的产物和方法。
发明内容
异常脂质代谢是CVD和NAFLD两者的标志特征。本文预期特定氨基酸的调节异常的代谢也在CVD和NAFLD的发病机理中起作用。本申请描述了N-酰基氨基酸,与脂肪酸缀合的氨基酸,用于诊断和治疗患有脂肪性肝炎、纤维化或心血管疾病状况中的一种或多种的主体的用途。
本文的第一个方面提供了用于治疗心血管疾病状况的方法。所述方法包括将治疗有效量的至少一种N-酰基氨基酸产物施用于患有心血管疾病状况的主体。心血管疾病(CVD)状况累及心脏和血管,且它们包括冠心病、脑血管疾病、周围动脉疾病、风湿性心脏病、先天性心脏病、主动脉瘤和深静脉血栓形成和肺栓塞。
本文的第二个方面提供了用于减少纤维化的方法。所述方法包括向患有纤维化的主体施用治疗有效量的至少一种N-酰基氨基酸产物。
本文的第三个方面提供了治疗脂肪性肝炎的方法。所述方法包括向患有脂肪性肝炎的主体施用治疗有效量的至少一种N-酰基氨基酸产物。
本文的第四个方面提供了N-酰基氨基酸产物和组合物,包括药物组合物。示例性N-酰基氨基酸产物包括,但不限于,N-酰基甘氨酸、N-酰基亮氨酸、N-酰基-D-亮氨酸、N-酰基甘氨酸-甘氨酸-亮氨酸、N-酰基甘氨酸-甘氨酸-D-亮氨酸、它们的药用盐或其至少两种的组合。
本文的第五个方面提供了诊断疾病状况例如心血管疾病状况、纤维化或脂肪性肝炎的方法。所述方法包括检测N-酰基氨基酸,例如,N-酰基甘氨酸、N-酰基亮氨酸和/或N-酰基-D-亮氨酸。
附图说明
图1.NASH中被抑制的N-酰基氨基酸的代谢和水平。(A)Pm20d1和(B)Glyat的肝表达的pPCR分析。(C)N-油酰基甘氨酸(C:18-Gly)、(D)N-花生四烯酰基(arachidonoyl)甘氨酸(C20:4-Gly)和(E)N-油酰基亮氨酸(C18:1-Leu)的肝浓度的LC-MS/MS分析。数据是平均值±SEM(n=8)。与CD比较*P<0.05;*P<0.01;***P<0.001;与NASH+H2O比较#P<0.05,##P<0.01###P<0.001。
图2A-2D.N-酰基氨基酸的肝水平与NASH严重程度之间的相关性。计算了在喂食CD(■)或NASH饮食并用H2O(对照,▲)、亮氨酸(▼)、甘氨酸(◆)、三肽甘氨酸-甘氨酸-亮氨酸(0.125mg/g/d,○)或三肽甘氨酸-甘氨酸-亮氨酸(0.5mg/g/d,●)治疗的小鼠(n=8-9)中的N-油酰基甘氨酸(C181-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)的肝水平和(A)通过脂质提取和TG定量评估的脂肪肝、(B)通过F4/80阳性面积评估的炎性浸润、(C)通过天狼猩红(Sirius Red)染色评估的纤维化评分和(D)NAFLD活动性评分(NAS)之间的Spearman相关性。
图3A-3C.N-酰基氨基酸的肝水平与循环心脏代谢(cardiometabolic)危险因素之间的相关性。计算了在喂食CD(■)或NASH饮食并用H2O(对照,▲)、亮氨酸(▼)、甘氨酸(◆)、三肽甘氨酸-甘氨酸-亮氨酸(0.125mg/g/d,○)或三肽甘氨酸-甘氨酸-亮氨酸(0.5mg/g/d,●)治疗的小鼠(n=8-9)中的N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)的肝水平和(A)ALT、(B)MCP-1和(C)TC的血浆水平之间的Spearman相关性。
图4.N-酰基氨基酸直接激活PPARα。(A,B)COS-1细胞用PPREx3-TK-萤光素酶、PPARα和Renilla共转染。转染后24小时,用10μM PPARα激动剂WY-14643、1mM甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸或10μM N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)或N-油酰基亮氨酸(C18:1-Leu)处理细胞24小时。萤光素酶活性被Renilla归一化。与CTL比较***P<0.001。
图5A-5C.N-酰基氨基酸的肝水平与PPARα靶基因表达之间的相关性。计算了在喂食CD(■)或NASH饮食并用H2O(对照,▲)、亮氨酸(▼)、甘氨酸(◆)、三肽甘氨酸-甘氨酸-亮氨酸(0.125mg/g/d,○)或三肽甘氨酸-甘氨酸-亮氨酸(0.5mg/g/d,●)治疗的小鼠(n=8-9)中的N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)的肝水平和(A)Ppargc1a、(B)Acot3和(C)Acadl的表达之间的Spearman相关性。
图6A-6D.N-酰基氨基酸经由FAO刺激脂质利用。(A,B)使用Seahorse XFe96分析仪评估的氧消耗率(OCR)和对FAO的依赖性。用10μM N-花生四烯酰基甘氨酸(C20:4-Gly)、N-油酰基亮氨酸(C18:1-Leu)或媒介物(乙醇,EtOH)刺激HepG2,且然后用6μM的CPT1抑制剂益托某西尔(etomoxir)处理(n=8)。(C,D)通过监控用10μM N-花生四烯酰基甘氨酸(C20:4-Gly)、N-油酰基亮氨酸(C18:1-Leu)或媒介物(乙醇,EtOH)处理的HepG2细胞中[3H]-乙酸盐(3.3μCi/ml)向TG中的并入评估的脂质生物合成和水解(n=6)。
图7.小鼠中NASH研究的实验设计。
图8A-8C.N-油酰基亮氨酸(C18:1-Leu)在不影响肥胖的情况下降低体重。第21至22周时基于NMR的身体组成分析(n=8):(A)体重,(B)脂肪(%),和(C)瘦体重(%)。数据是平均值±SEM。通过单因素方差分析继之以Tukey事后(Tukey post hoc)检验或通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较***P<0.001;与NASH比较###P<0.001;与NASH+C18:1比较AAAP<0.001。
图9A-9D N-油酰基亮氨酸(C18:1-Leu)对NASH中的全身能量平衡没有显著影响。在第21至22周使用综合实验室动物监控系统(CLAMS)评估代谢参数(n=8):(A)呼吸换气率(RER),(B)能量消耗(EE),(C)摄食量,和(D)总活动。数据是平均值±SEM。通过单因素方差分析继之以Tukey事后检验或通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较*P<0.05,**P<0.01,***P<0.001。
图10A-10B.N-油酰基亮氨酸(C18:1-Leu)显著降低肝肿大。终点处的(A)肝的大体形态学,和(B)肝重量与体重比(n=8-10)。数据是平均值±SEM。通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较***P<0.001,与NASH比较##P<0.01;与NASH+C18:1比较^P<0.05。
图11A-11C.N-油酰基亮氨酸(C18:1-Leu)降低循环肝酶。终点处的循环肝酶:(A)丙氨酸转氨酶(ALT)、(B)天冬氨酸转氨酶(ASP)和(C)碱性磷酸酶(ALP)(n=8-10)。数据是平均值±SEM。通过单因素方差分析继之以Tukey事后检验或通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较**P<0.01,***P<0.001;与NASH比较#P<0.05,##P<0.01。
图12A-12D.N-油酰基亮氨酸(C18:1-Leu)显著降低饮食诱导的NASH。(A)肝的苏木精和伊红(H&E)组织学(比例尺=50μm)。(B-E)H&E组织学用于评分(B)脂肪肝(0-3)、(C)小叶炎症(0-3)和(D)肝细胞气球样变(hepatocyte ballooning)(0-2)。NAFLD活动性评分(NAS)计算为上述评分的和(n=8-10)。数据是平均值±SEM。通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较***P<0.001,与NASH比较#P<0.05;与NASH+C18:1比较^P<0.05。
图13A-13B.N-油酰基亮氨酸(C18:1-Leu)显著降低脂肪肝。(A)肝的油红O(ORO)组织学(比例尺=100μm)。(B)血浆总胆固醇(TC)(n=8-10)。数据是平均值±SEM。通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD.比较**P<0.01,***P<0.001。
图14A-14C.N-油酰基亮氨酸(C18:1-Leu)显著降低NASH饮食诱导的肝和全身炎症。(A)肝的F4/80免疫组织化学(比例尺=50μm)。(B)血浆C-C基序趋化因子配体2(CCL2),和(C)CCL5(n=8-10)。数据是平均值±SEM。通过单因素方差分析继之以Tukey事后或通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD比较**P<0.01,***P<0.001,与NASH比较#P<0.05。
图15A-15B.N-油酰基亮氨酸(C18:1-Leu)显著降低NASH饮食诱导的肝纤维化。(A)肝的天狼猩红组织学(比例尺=50μm)。(B)基于天狼猩红组织学的纤维化评分(n=8-10)。数据是平均值±SEM。通过Kruskal-Wallis检验继之以Dunn氏事后检验来比较统计差异。与SD.比较**P<0.01,***P<0.001,与NASH比较#P<0.05。
图16.小鼠中动脉粥样硬化研究的实验设计。
图17A-17B.N-油酰基亮氨酸(C18:1-Leu)治疗对动脉粥样硬化小鼠中的体重和血浆胆固醇没有显著影响。终点处的(A)体重和(B)血浆总胆固醇(TC)。数据是平均值±SEM。通过非配对t检验比较统计差异。
图18.N-油酰基亮氨酸(C18:1-Leu)显著降低动脉粥样硬化。主动脉窦的H&E组织学用于定量斑块面积。数据是平均值±SEM。通过Mann Whitney检验来比较统计差异。*P<0.05。
图19.N-油酰基亮氨酸(C18:1-Leu)显著减少病变巨噬细胞。主动脉窦的Mac-2免疫组织化学用于定量病变巨噬细胞的含量。数据是平均值±SEM。通过Mann Whitney检验来比较统计差异。**P<0.01。
具体实施方式
N-酰基氨基酸产物是其中长链脂肪酸的酰基部分与氨基酸共价连接的产物。
本文中N-酰基氨基酸产物的氨基酸组分可以是甘氨酸或亮氨酸,或包含甘氨酸和亮氨酸的肽。肽可以是,例如,二肽或三肽。除甘氨酸之外,常见的氨基酸都含有至少一个手性碳原子。亮氨酸以两种形式存在,称为L-异构体和D-异构体的立体异构体。大多数天然存在的蛋白和肽仅仅由L-异构形式组成。除非指定D-亮氨酸,否则本文含亮氨酸的N-酰基氨基酸产物包含L-亮氨酸。
示例性二肽氨基酸组分是甘氨酸-甘氨酸、甘氨酸-亮氨酸、甘氨酸-D-亮氨酸、亮氨酸-亮氨酸、D-亮氨酸-亮氨酸、D-亮氨酸-D-亮氨酸和亮氨酸-D-亮氨酸。
示例性三肽氨基酸组分是甘氨酸-甘氨酸-亮氨酸和甘氨酸-甘氨酸-D-亮氨酸。
本文中N-酰基氨基酸产物的长链脂肪酸组分可以是多不饱和脂肪酸或硝基脂肪酸。
示例性的N-酰基氨基酸产物是N-棕榈酰基甘氨酸。
示例性的N-酰基氨基酸产物是N-硬脂酰基甘氨酸。
示例性的N-酰基氨基酸产物是N-油酰基甘氨酸。
示例性的N-酰基氨基酸产物是N-二十二碳六烯酰基甘氨酸。
示例性的N-酰基氨基酸产物是N-花生四烯酰基甘氨酸。
示例性的N-酰基氨基酸产物是N-棕榈酰基亮氨酸。
示例性的N-酰基氨基酸产物是N-硬脂酰基亮氨酸。
示例性的N-酰基氨基酸产物是N-油酰基亮氨酸。
示例性的N-酰基氨基酸产物是N-二十二碳六烯酰基亮氨酸。
示例性的N-酰基氨基酸产物是N-花生四烯酰基亮氨酸。
示例性的N-酰基氨基酸产物是N-棕榈酰基D-亮氨酸。
示例性的N-酰基氨基酸产物是N-硬脂酰基D-亮氨酸。
示例性的N-酰基氨基酸产物是N-油酰基D-亮氨酸。
示例性的N-酰基氨基酸产物是N-二十二碳六烯酰基D-亮氨酸。
示例性的N-酰基氨基酸产物是N-花生四烯酰基D-亮氨酸。
示例性的N-酰基氨基酸产物是N-棕榈酰基甘氨酸-甘氨酸-亮氨酸。
示例性的N-酰基氨基酸产物是N-硬脂酰基甘氨酸-甘氨酸-亮氨酸。
示例性的N-酰基氨基酸产物是N-油酰基甘氨酸-甘氨酸-亮氨酸。
示例性的N-酰基氨基酸产物是N-二十二碳六烯酰基甘氨酸-甘氨酸-亮氨酸。
示例性的N-酰基氨基酸产物是N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸。
示例性的N-酰基氨基酸产物是N-棕榈酰基甘氨酸-甘氨酸-D-亮氨酸。
示例性的N-酰基氨基酸产物是N-硬脂酰基甘氨酸-甘氨酸-D-亮氨酸。
示例性的N-酰基氨基酸产物是N-油酰基甘氨酸-甘氨酸-D-亮氨酸。
示例性的N-酰基氨基酸产物是N-二十二碳六烯酰基甘氨酸-甘氨酸-D-亮氨酸。
示例性的N-酰基氨基酸产物是N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸。
本文中N-酰基氨基酸产物的脂肪酸组分可以是多不饱和脂肪酸(PUFA),例如亚油酸、共轭亚油酸或ω3脂肪酸。示例性的ω3脂肪酸包括,但不限于,二十二碳六烯酸、α-亚麻酸或二十碳五烯酸(eicosapentanoic acid)。本文中N-酰基氨基酸产物的脂肪酸组分可以是ω3脂肪酸的代谢物,例如呋喃脂肪酸或消退素(resolvin)。示例性的呋喃脂肪酸是3-羧基-4-甲基-5-丙基-2-呋喃丙酸。示例性的消退素是消退素D。
本文中N-酰基氨基酸产物的脂肪酸组分可以是硝基脂肪酸,例如10-硝基-十八碳-9-烯酸、9-硝基-十八碳-9-烯酸、硝化ω-3脂肪酸(包括,但不限于,亚麻酸、α亚麻酸、二十碳五烯酸、二十二碳五烯酸、二十二碳六烯酸(docosahexanoic acid)和十八碳四烯酸(stearidonic acid))、硝化ω-5脂肪酸(包括,但不限于,肉豆蔻脑酸)、硝化ω-6脂肪酸(包括,但不限于,亚油酸、γ-亚油酸、二高-γ-亚油酸(dihomo-gamma-linoleic acid)和花生四烯酸)、硝化ω-7脂肪酸(包括,但不限于,共轭亚油酸和棕榈油酸)或硝化ω-9脂肪酸(包括,但不限于,油酸和芥酸)。
还提供了不同N-酰基氨基酸产物的组合。例如,提供了N-花生四烯酰基甘氨酸、N-油酰基亮氨酸和N-油酰基D-亮氨酸中两种或更多种的组合。作为又另一个实例,提供了N-花生四烯酰基甘氨酸和N-油酰基亮氨酸的组合。作为另一个实例,提供了N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸和N-油酰基甘氨酸-甘氨酸-D-亮氨酸中的两种或更多种的组合。作为又进一步的实例,提供了N-花生四烯酰基甘氨酸、N-油酰基亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸和N-油酰基甘氨酸-甘氨酸-D-亮氨酸中的两种或更多种的组合。
本文的N-酰基氨基酸产物还包括药学上可接受的盐。药学上可接受的盐是本领域众所周知的。例如,Berge等人在J.Pharmaceutical Sciences,66:1-19(1977)中详细描述了药学上可接受的盐。这种盐的实例包括金属盐、铵盐、与有机碱的盐、与无机酸的盐、与有机酸的盐、与碱性或酸性氨基酸的盐等。金属盐的实例包括碱金属盐如钠盐、钾盐等;碱土金属盐如钙盐、镁盐、钡盐等;铝盐等。与有机碱的盐的实例包括与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己胺、N,N-二苄基乙二胺等形成的盐。与无机酸的盐的实例包括与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸的盐的实例包括与甲酸、乙酸、三氟乙酸、苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、对甲苯磺酸等形成的盐。
本文的N-酰基氨基酸产物或其药学上可接受的盐可以作为其原始合成形式的前药合成和/或施用。前药是在活体内的生理条件下,通过由于酶、胃酸等反应转化为本文所述产物的化合物,即,根据酶由于氧化、还原、水解等转化为甘氨酸三肽分子或其药学上可接受的盐的化合物;由于胃酸等通过水解等转化为甘氨酸三肽分子的化合物。参见,例如,IYAKUHIN no KAIHATSU(Development of Pharmaceuticals),第7卷,Design ofMolecules,第163-198页,由HIROKAWA SHOTEN出版(1990)。
本文的N-酰基氨基酸产物的肽组分可以通过本领域已知的肽合成方法产生。肽合成法可以采用缩合反应,例如,在固相合成方法或液相合成方法中。如果产生的产物具有保护基团,则除去保护基团。已知的肽合成方法的例子包括描述于下述中的方法:M.Bodanszky和M.A.Ondetti:Peptide Synthesis,Interscience Publishers,New York(1966);Schroeder和Luebke:The Peptide,Academic Press,New York(1965);NobuoIzumiya等人:Peptide Gosei-no-Kiso to Jikken(Basics and experiments of peptidesynthesis),由Maruzen Co.出版(1975);Haruaki Yajima和Shunpei Sakakibara:Seikagaku Jikken Koza(Biochemical Experiment)1,Tanpakushitsu no Kagaku(Chemistry of Proteins)IV,205(1977);和Haruaki Yajima编:Zoku Iyakuhin noKaihatsu(A sequel to Development ofPharmaceuticals),第14卷,Peptide Synthesis,由Hirokawa Shoten出版。
本文提供的组合物包含至少一种N-酰基氨基酸产物,或包含N-酰基氨基酸产物的组合。
本文提供的药物组合物包含药学上可接受的赋形剂和至少一种N-酰基氨基酸产物或两种或更多种N-酰基氨基酸产物的组合。
适合于递送本文的N-酰基氨基酸产物的药物组合物及其制备方法对本领域技术人员而言是显而易见的。Remington’s Pharmaceutical Sciences,The Science andPractice of Pharmacy,第22版,Lippincott Williams&White,Baltimore,MD(2013)提供了示例性的标准注意事项和方法。
取决于特定的施用方式和剂型,本文的药物组合物与药学上可接受的赋形剂一起配制,例如载体、溶剂、稳定剂、佐剂、稀释剂等。可以包含药物组合物组分用于修饰、维持或保持例如组合物的pH、摩尔渗透压浓度、黏度、透明度、颜色、等渗性、气味、无菌、稳定性、溶解或释放速率、吸附或渗透。通常配制组合物以实现生理相容的pH,并且范围为约3的pH至约11的pH、约pH 3至约pH 7或约pH 5.0至约pH 8,这取决于制剂和施用途径。
合适的赋形剂包括,例如,无菌液体,例如水和油,包括石油、动物、植物或合成起源的那些,例如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水是典型的赋形剂。盐水溶液(包括,但不限于,氯化钠溶液)和葡萄糖和甘油水溶液可以用作液体赋形剂,特别是用于可注射溶液。额外的合适的药用赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、rich、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。预期的赋形剂的更大列表包括,但不限于,氨基酸(例如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸);抗微生物剂;抗氧化剂(如抗坏血酸、亚硫酸钠或亚硫酸氢钠);缓冲液(例如硼酸盐、碳酸氢盐、Tris HCl、柠檬酸盐、磷酸盐、其他有机酸);填充剂(如甘露糖醇或甘氨酸)、螯合剂(如乙二胺四乙酸(EDTA));络合剂(如咖啡因、聚乙烯吡咯烷酮、β环糊精或羟丙基β环糊精);填料;单糖;二糖和其他碳水化合物(如葡萄糖、甘露糖、羟烷基纤维素、羟烷基甲基纤维素或糊精);蛋白(如血清清蛋白、明胶或免疫球蛋白);着色剂;调味剂和稀释剂;乳化剂;亲水性聚合物(如聚乙烯吡咯烷酮);低分子量多肽;成盐抗衡离子(如钠);防腐剂(例如苯扎氯铵、苯甲酸、水杨酸、硫柳汞、苯乙醇、羟苯甲酯、羟苯丙酯、氯己定、山梨酸或过氧化氢);溶剂(例如甘油、丙二醇或聚乙二醇);糖醇(如甘露糖醇或山梨糖醇);悬浮剂;表面活性剂或湿润剂(例如普朗尼克类(pluronics)、PEG、失水山梨糖醇酯、聚山梨醇酯如聚山梨醇酯20、聚山梨醇酯80、triton、氨丁三醇、卵磷脂、胆固醇、泰洛沙泊(tyloxapal));稳定性增强剂(蔗糖或山梨糖醇);张力增强剂(例如碱金属卤化物(在一个方面,氯化钠或氯化钾、甘露糖醇山梨糖醇);递送媒介物;稀释剂;和/或载体分子,其包括大的、缓慢代谢的大分子,例如蛋白、多糖、聚乳酸、聚乙醇酸(polyglycolic acid)、聚合氨基酸、氨基酸共聚物和无活性病毒颗粒。
本文的药物组合物可以采用溶液、混悬剂、乳剂、片剂、丸剂、胶囊、粉末、缓释制剂等形式。本文的药物组合物可以配制用于N-酰基氨基酸产物的立即释放和/或修饰释放。
本文的药物组合物通过任何合适的途径施用,例如,通过静脉内、口服、眼、皮内、皮下、腹膜内或肌内途径。预期通过口服途径施用是使用本领域已知的将使N-酰基氨基酸在胃肠道中的降解减至最小的递送媒介物完成的,包括,但不限于,小球体、脂质体、肠溶干乳剂(enteric-coated dry emulsions)、片剂或纳米颗粒。
用于向有需要的主体施用N-酰基氨基酸产物或产物组合的试剂盒包括本文所述的N-酰基氨基酸产物组合物、用于使用N-酰基氨基酸产物组合物的说明书以及任选的额外的第二治疗剂或疗法。
本文的示例性原液组合物包含在100%乙醇中稀释至50mg/ml的终浓度的N-花生四烯酰基甘氨酸和/或N-油酰基亮氨酸。N-花生四烯酰基甘氨酸贮藏于-80℃,且n-油酰基亮氨酸贮藏于-20℃。然后通过以4:15:81(v:v:v)的比例在100%乙醇和无菌盐水溶液(0.9%NaCl)的混合物中稀释从原液组合物新鲜制备本文的示例性药物组合物,以产生2mg/ml浓度的N-酰基氨基酸产物的组合物。
本文包含N-酰基甘氨酸-甘氨酸-亮氨酸和/或N-酰基甘氨酸-甘氨酸-D-亮氨酸的示例性原液组合物包括在由10mM谷氨酸、2%甘氨酸、1%蔗糖和0.01%聚山梨醇酯20组成至pH 4.25的制剂缓冲液中制备的冻干饼。然后通过用一定体积的无菌稀释剂,例如,无菌等渗盐水或水,例如0.5mL至约10mL,例如2.2mL无菌水重构来制备本文的示例性药物组合物,以产生1g/mL至约100g/mL浓度的N-酰基氨基酸产物的组合物。
提供了向主体施用包含治疗有效量的本文所述的N-酰基氨基酸产物或产物组合的药物组合物的方法。
主体可以是哺乳动物,且哺乳动物可以是,例如,实验室动物或人,且人主体包括成年、青少年和儿科主体。
如本文所用的,“治疗有效量”指足以表现出可检测的治疗效果的N-酰基氨基酸产物的量。通过临床状况的改善和/或与状况有关的特定症状或事件的发展的减少、消除或抑制来检测效果。主体的精确有效量将取决于主体的体重、大小和健康状况;状况的特性和程度;以及选择用于施用的产物或产物组合。治疗有效量通过在临床医师的技能和判断范围内的常规实验来确定。
本文的药物组合物可以通过如上文所指出的任何合适的途径施用于主体。例如,本发明的组合物可以通过静脉内、口服、眼、皮内、腹膜内、皮下或肌内途径施用。
本领域技术人员理解,有效量部分地取决于递送的分子、使用组合物的适应症、施用途径和主体的大小(体重、体表面或器官大小)和状况(年龄和一般健康状况)而变化。因此,临床医师可以滴定(titer)剂量并修改施用途径以获得最佳治疗效果。治疗有效量可以是包括,但不限于,约1mg/kg-约10,000mg/kg、约1mg/kg-约1,000mg/kg、约0.1mg/kg-约1,000mg/kg、约1mg/kg-约1,000mg/kg、约1,000mg/kg-约10,000mg/kg或约1mg/kg-约500mg/kg的剂量,根据主体体重计算的。示例性治疗有效剂量为约100mg-约200g。示例性治疗有效剂量为约100mg/kg-约200mg/kg。另一个示例性治疗有效剂量为约0.01mg/kg-约200mg/kg。另一个示例性治疗有效剂量为约10mg/kg-约200mg/kg。另一个示例性治疗有效剂量为约1mg-约10mg。剂量可以每天一次、每天两次或三次、每隔一天、每周两次、每周一次、每月一次或每半年一次给予。递送也可以通过连续输注。本文所述的方法可用于治疗,例如,心血管疾病状况、脂肪性肝炎和纤维化。
术语“治疗(treating)”(或所述词语的其他形式,例如“治疗(treatment)”或“治疗(treat)”)在本文中用于意指施用本发明的组合物缓和主体的状况和/或减少、抑制或消除与状况有关的特定症状或事件。因此,术语“治疗”包括防止主体发生状况,特别是当主体倾向于获得状况时;减少或抑制状况;和/或改善或逆转状况。在本发明的方法涉及预防状况的范围内,应理解术语“预防”不要求完全避免状况。
心血管疾病状况是心脏和血管的疾病状况,包括,但不限于:冠心病-供应心肌的血管的疾病;脑血管疾病-供应脑的血管的疾病;周围动脉疾病-供应臂和腿的血管的疾病;风湿性心脏病-由链球菌细菌引起的来自风湿热的对心肌和心脏瓣膜的损害;先天性心脏病-出生时存在的心脏结构畸形;主动脉瘤-主动脉壁异常突起;和深静脉血栓形成和肺栓塞-腿静脉中的血凝块,其可以移位并移动到心和肺。心血管疾病状况的治疗导致以下一种或多种:可通过标准技术检测到的缓和,包括但不限于:动脉粥样硬化斑块的减少(例如,通过超声成像证明的)、心脏功能的增加、心肌肥大的减少[例如,通过超声成像、计算机体层摄影术扫描、磁共振成像或生物标记物例如肌钙蛋白和/或BMP(或其他生物标记物,例如Tang等人,Circulation,116:e99-e109(2007)的第e101页列出的那些)的分析证明的]、血压的降低、炎性状态的减少(例如,通过分析循环炎性标记物如MCP-1、C-反应蛋白、血清淀粉状A蛋白、热休克蛋白65、白细胞介素-6和白细胞黏附分子证明的)和主动脉直径减小。
通过本文治疗缓和的与心血管疾病状况有关的事件包括,但不限于,心力衰竭、代偿失调(例如,心或肝的)、心肌梗死和动脉瘤。
脂肪性肝炎是一种类型的脂肪肝病,其特征在于同时存在肝中脂肪累积的肝的炎症。非酒精性脂肪性肝炎(NASH)对肝的损害类似于由大量饮酒引起的脂肪性肝炎中见到的损害。在宏观和微观上,NASH特征在于小叶和/或门静脉炎症、不同程度的纤维化、肝细胞死亡和病理性血管发生。在最严重的情况下,NASH可进展至肝硬化、肝细胞癌和肝衰竭。本文的脂肪性肝炎治疗方法可以通过主体的NAFLD活动性评分来监控。可以根据Kleiner等人,Hepatology,41:1313-1321(2005)的标准计算NAFLD活动性评分(NAS)。NAS评分0-2不被认为是对于NASH诊断性的,NAS评分3-4被认为是对于NASH非诊断性的、模棱两可的或阳性的,而NAS评分5-8主要被认为是对于NASH诊断性的。来自可能患有NASH的主体的连续肝活组织检查可用于评估NAS评分的变化并用作疾病状态变化的指示。增加的评分提示进展,不变的评分提示稳定化,而下降的评分提示NASH的消退。本文中脂肪性肝炎的治疗导致一种或多种可通过标准技术检测的缓和,包括,但不限于:肝脂肪的减少(例如,通过如用油红O的脂质染色、三酰甘油的生化分析或超声成像证明的)、炎性状态的减少(例如,通过如Kleiner,上文的表1中提及的组织学,或循环炎性标记物如MCP-1、C-反应蛋白、血清淀粉状A蛋白、热休克蛋白65、白细胞介素-6和白细胞黏附分子的分析证明的)、受损的肝细胞的减少(例如,通过组织学证明的)和动脉粥样硬化斑块的减少(例如,通过超声成像证明的)。
纤维化是病理性伤口愈合,其中结缔组织取代正常的实质组织至导致广泛的组织重新塑造和永久性瘢痕组织的形成的程度。细胞外基质组分例如成纤维细胞产生的胶原蛋白的过度累积导致永久性纤维化瘢痕的形成。纤维化评分为0-4(0:无纤维化;1:窦周或门静脉纤维化;2:窦周和门静脉纤维化;3:桥接纤维化;4:肝硬化)。参见,例如,Kleiner,上文的表1。增加的评分提示进展,不变的评分提示稳定化,而下降的评分提示纤维化的消退。本文中纤维化的治疗导致肝、心、肺、肾、皮肤和脂肪组织中的一个或多个中可通过标准技术检测的纤维化的减少。本文中纤维化的治疗可导致胆管、胆囊或与胆汁产生和运输有关的其他结构中的一个或多个中可通过标准技术检测的纤维化的减少。例如,胶原蛋白的累积常规地通过如用苦味酸天狼猩红(Picrosirius Red)或Masson三色染色,或通过羟脯氨酸的检测来检测。
本文的治疗可包括用一种或多种N-酰基氨基酸产物与第二治疗剂例如其他脂质降低剂和/或葡萄糖降低剂组合的治疗。其他脂质降低剂和/或葡萄糖降低剂包括,但不限于,他汀类、纤维酸、SGLT2i、二甲双胍和肠降血糖素。
本文的诊断方法包括检测主体中的N-酰基氨基酸,例如,N-酰基甘氨酸、N-酰基亮氨酸和/或N-酰基-D-亮氨酸。本文的诊断预期包括初步诊断和/或监控疾病状况的进展/消退状态。这种N-酰基氨基酸的肝水平与脂肪肝、纤维化、炎症和高胆固醇血症的严重程度呈负相关。
实施例
本发明通过以下实施例进行举例说明,其包括以小鼠中脂肪性肝炎和纤维化共存为特征的NASH的长期饮食模型。通过RNA-测序继之以qPCR确认对肝基因表达进行的无偏分析揭示,编码催化脂肪酸和各种氨基酸(含有肽酶M20结构域的1,Pm20d1)且特别地与甘氨酸(甘氨酸-N-酰基转移酶,Glyat)缩合的酶的基因在NASH中被抑制。靶向的代谢物组学表明,N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)的水平在来自患有NASH的小鼠的肝中显著降低。这种降低通过用游离甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸的长期治疗来救济。上述N-酰基氨基酸的肝水平与脂肪肝、纤维化、炎症和高胆固醇血症的严重程度显著地且负相关,而与脂肪酸β-氧化(FAO)的主要调节物过氧化物酶体增殖物激活受体-α(PPARα)的靶基因的表达正相关。应用Seahorse和萤光素酶测定,发现N-酰基氨基酸直接激活PPARα,刺激线粒体呼吸和FAO。总之,N-酰基氨基酸介导肝脂质利用并改善能量代谢,且因此构成了对抗CVD、脂肪性肝炎和纤维化的有效治疗方法。
实施例1
三肽甘氨酸-甘氨酸-亮氨酸通过调节肝代谢和N-酰基氨基酸水平来保护以防
NASH
为了探索三肽甘氨酸-甘氨酸-亮氨酸对NASH的治疗潜力,使用了一种模拟晚期NAFLD的实验方法。如所述的,C57BL/6J小鼠被喂食高脂肪、高果糖和高胆固醇饮食(NASH饮食)12周。确认NASH后,将小鼠随机化以接受口服0.125或0.5mg/g/天的三肽甘氨酸-甘氨酸-亮氨酸、等量的亮氨酸、甘氨酸或H2O达在NASH饮食上额外12周。喂食低脂肪对照饮食(CD)并施用H2O的小鼠充当对照。
方法
动物
动物程序由密歇根大学(University of Michigan)(U-M)的机构动物护理和使用委员会(Institutional Animal Care&Use Committee)批准(PRO00008239),并按照机构指南进行。七周大的雄性C57BL/来自Jackson Laboratories。习服一周后,小鼠不限量地喂食低脂肪对照饮食(CD,Research Diets D17072805,10%脂肪)或高脂肪、高果糖和高胆固醇饮食(NASH饮食,Research Diets D17010103)。确认NASH后,将小鼠随机化以接受0.125或0.5mg/g/天的口服三肽甘氨酸-甘氨酸-亮氨酸(北京双鹭药业股份有限公司)、等量的亮氨酸(0.17mg/g/天,Sigma-AldrichL8912)、甘氨酸(0.33mg/g/天,Sigma-Aldrich G5417)或H2O达在NASH饮食上额外12周。
组织学和免疫组织化学
所有组织学程序均由U-M的体内动物中心(IVAC)组织学实验室(In Vivo AnimalCore(IVAC)Histology Laboratory)执行。技术人员对实验组不知情。使用自动VIP5或VIP6组织处理机(TissueTek,Sakura-Americas)将福尔马林固定的组织通过分段酒精处理并用二甲苯透明处理继之以用熔化的石蜡浸润。使用Histostar包埋工作站(EmbeddingStation)(ThermoFisher Scientific),然后在M355S轮转切片机(ThermoFisherScientific)上以4μm厚度对组织进行切片,并封固在载玻片上。对载玻片进行苏木精和伊红染色(H&E,ThermoFisher Scientific)。对于天狼猩红染色,载玻片用0.2磷钼酸处理3分钟,并转移到在苦味酸中饱和的0.1%天狼猩红(Rowley Biochemical Inc.)中达90分钟,然后转移到0.01N盐酸达3分钟。
冷冻的切片处理用于油红O染色。福尔马林固定的肝样品于4℃在20%蔗糖中冷冻保护过夜,吸干,然后在OCT化合物(Tissue-Tek,Cat#4583)中液氮骤冻并于-80℃贮藏,直到准备好用于冷冻切片为止。在切片前,将冷冻的块增到约-20℃,然后在恒冷切片机(Cryotome)SME(Thermo-Shandon,Cat#77200227)上以5μm进行切片。载玻片于-80℃贮藏,直到染色为止。在染色前,将肝载玻片解冻至室温达30分钟。载玻片在10%中性缓冲福尔马林(Neutral Buffered Formalin)中后固定(post-fixed)20分钟,在DDW中漂洗,继之以在放置入工作油红O-异丙醇染色剂(Rowley Biochemical Inc.,H-503-1B)之前在60%异丙醇中漂洗5分钟。然后在60%异丙醇中漂洗载玻片,继之以DDW的3次更换。然后,载玻片在哈里斯苏木精中进行核复染,并封固在Aqua-Mount(Lerner Laboratories,Cat#13800)水性封固剂中。
在阻断内源性过氧化物酶和非特异性结合的情况下,在IntelliPATH FLX自动免疫组织化学染色机(stainer)(Biocare Medical)上进行免疫组织化学染色,继之以使用基于辣根过氧化物酶无生物素聚合物的商业检测系统进行检测,使用二氨基联苯胺色原进行显示,以及使用苏木精进行核复染。特异于F4/80,(Bio-Rad ABD Serotec,Cat#MCA497),大鼠单克隆第一抗体(克隆CI:A3-1)在DaVinci稀释剂(DaVinci Diluent)(BiocareMedical,Cat#PD900)中稀释至1:400并温育60分钟,继之以使用Rat-on-Mouse HRP-Polymer,(Biocare Medical,Cat#RT517)两步探针-聚合物分别温育10分钟和30分钟进行检测。
NAFLD活动性和纤维化的评分
H&E染色用于对NAFLD活动性评分(NAS)进行评分。脂肪变性评分为0-3(0:<5%脂肪变性;1:5-33%;2:34-66%;3:>67%)。肝细胞气球样变评分为0-2(0:正常肝细胞,1:具有苍白色细胞质的正常大小的,2:苍白色且增大的肝细胞,至少2-倍)。基于在20X计数的炎症病灶将小叶炎症评分为0-2(0:无,1:<2个病灶;2:≥2个病灶)。NAS计算为脂肪变性、肝细胞气球样变和小叶炎症评分的和。使用天狼猩红染色从0-4对肝纤维化进行评分(0:无纤维化;1:窦周或门静脉纤维化;2:窦周和门静脉纤维化;3:桥接纤维化;4:肝硬化)。
血浆分析
ALT和AST的临床化学测定由U-M IVAC在Liasys 330化学分析仪(AMSDiagnostics)上使用制造商提供的试剂和规程进行。使用Wako Diagnostics试剂盒(999-02601)测量血浆总胆固醇。使用小鼠CCL2/JE/MCP-1Quantikine ELISA试剂盒(R&DSystems)测量血浆MCP-1。
RNA-测序和数据分析
使用QIAGEN的RNeasy试剂盒(QIAGEN)从小鼠肝样品中提取总RNA。文库制备和测序由U-M DNA测序中心(U-M DNA Sequencing Core)进行。使用TapeStation(Agilent,Santa Clara,CA)评估RNA的质量。所有样品都具有>8.5的RNA完整值(RNA integritynumber)(RINs)。使用具有聚腺苷酸mRNA磁分离模块(Poly(A)mRNA Magnetic IsolationModule)(NEB,E7490L)和用于Illumina Unique dual的NEBNext多重寡核苷酸(MultiplexOligos)(NEB,E6440L)的用于Illumina的NEBNext Ultra II Directional RNA文库制备试剂盒(Library Prep Kit)(NEB,E7760L)制备样品,其中使10ng-1μg总RNA经受mRNA聚腺苷酸纯化。然后将mRNA片段化并使用逆转录酶和dUTP混合物复制为第一链cDNA。样品经历末端修复(end repair)和dA-加尾步骤,继之以NEBNext衔接子的连接。通过PCR纯化和富集产物以产生最终的cDNA文库。通过TapeStation(Agilent)和qPCR使用用于Illumina测序平台的Kapa文库定量试剂盒(Kapa Biosystems,KK4835)检查最终文库的质量和数量。文库在NovaSeq 6000测序系统(Illumina)上进行双端(paired-end)测序。
通过FastQC v0.11.8(https://www.bioinformatics.babraham.ac.uk/projects/fastqc/)检查原始FASTQ文件的质量。Trimmomatic v.0.35用于利用以下参数整理低质量读长:SLIDINGWINDOW:4:20MINLEN:25。然后使用HISAT2 v.2.1.0.13将所得到的高质量读长作图到小鼠参考基因组(GRCm38.90)。基于GRCm38.90基因组注释,使用HTSeq-counts v0.6.0进行基因表达定量。然后将R软件包DESeq2用于鉴定显著差异表达的基因(DEG)。我们将具有小于0.05的调整的P值以及大于2的绝对倍数变化的基因视为显著的DEG。然后使用clusterProfiler软件包分别分析显著富集的KEGG途径的上调和下调的DEGs。富集的显著性由右侧(right-tailed)Fisher精确检验继之以Benjamini-Hochberg多重检验调整确定。
定量实时PCR分析
使用QIAGEN的RNeasy试剂盒(QIAGEN)从小鼠肝样品中提取总RNA。用SuperScriptIII和随机引物(Invitrogen)将RNA逆转录成cDNA。使用iQ SYBR Green Supermix(Bio-Rad)和归一化的ΔΔCt阈值循环方法,通过实时PCR系统(Bio-Rad)评估特定转录物。基因表达相对于Gapdh归一化。用于qPCR的引物对是从Integrated DNA Technologies获得的,且如下所列:
肝分析
肝被迅速从实施安死术的小鼠取出,在液氮中骤冻,并保持于-80℃。用于检测和定量N-酰基氨基酸的LC-MS/MS方法由U-M药物代谢动力学和质谱分析法中心(U-MPharmacokinetics and Mass Spectrometry Core)开发。技术人员对实验组不知情。将肝中N-酰基氨基酸的水平相对于组织重量归一化并表示为ng/g肝组织。对于TG定量,将冷冻的肝样品(100mg)在PBS中匀浆并离心(14,000RPM,20分钟)。收集上清液并使用Bio-RadBradford测定分析蛋白浓度。为了评估肝脂质组成,使用3:2比例(v:v)的己烷(≥99%,Sigma-Aldrich 32293)和异丙醇(≥99.5%,Fisher Scientific A426-4)从上清液中提取脂质,且使己烷相蒸发48小时。使用市售的Wako Diagnostics试剂盒(994-02891)通过分光光度法测定肝TG的量。
结果
在终点处,NAFLD标记物丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的血浆水平的升高被甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸减弱。因此,甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸显著减少了NASH饮食诱导的肝肿大,且组织学分析揭示了具有由0.5mg/g/天三肽甘氨酸-甘氨酸-亮氨酸显著降低的NAFLD活动性评分(NAS)的较低的脂肪肝、炎症(F4/80巨噬细胞染色)和纤维化(天狼猩红染色)。
通过RNA-测序对肝基因表达进行的无偏分析揭示,编码催化脂肪酸和各种氨基酸(含有肽酶M20结构域的1,Pm20d1)且特别地与甘氨酸(甘氨酸-N-酰基转移酶,Glyat)缩合的酶的基因在患有NASH的小鼠中被下调,其被三肽甘氨酸-甘氨酸-亮氨酸治疗逆转。这些结果通过qPCR分析得到证实(图1A,B)。因此,靶向的代谢物组学揭示,N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)的水平在来自患有NASH的小鼠的肝中显著降低,其通过用甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸的长期治疗来救济(图1C-E)。
实施例2
N-酰基氨基酸的肝水平与脂肪性肝炎、纤维化和心血管疾病的标记物有关为了检查N-酰基氨基酸和NASH之间的关系,我们分析了N-酰基氨基酸的来自实施例1小鼠的肝水平与NASH严重程度指标即脂肪肝(肝三酰甘油的定量,TG)、炎症(F4/80免疫组织化学)、纤维化(天狼猩红染色)和总NAS之间的相关性。我们发现,N-酰基氨基酸的肝水平与脂肪肝(图2A)、炎症(图2B)、纤维化(2C)和NAS(图2D)显著地且负相关。在N-花生四烯酰基甘氨酸(C20:4-Gly)水平与上述指标之间发现了最显著的负相关(P<0.0001)。
然后,为了检查N-酰基氨基酸与其他心脏代谢危险因素之间的关系,我们分析了N-酰基氨基酸的实施例1的小鼠中肝水平与ALT(肝损伤标记物)、单核细胞趋化蛋白1(MCP-1,炎性标记物)和总胆固醇(TC,CVD的最强危险因素之一)的血浆水平之间的相关性。类似于NASH指标(图2A-D),N-酰基氨基酸的肝水平与ALT、MCP-1和TC显著地且负相关,对于N-花生四烯酰基甘氨酸(C20:4-Gly)发现了最显著的相关性(P<0.0001)(图3A-C)。
实施例3
N-酰基氨基酸直接激活PPARα
实施例1中描述的无偏RNA-测序分析揭示,主要的促炎和促纤维化(pro-fibrotic)途径在患有NASH的小鼠的肝中富集。相比之下,在来自食用NASH饮食并用三肽甘氨酸-甘氨酸-亮氨酸治疗的小鼠的肝中,最显著的上调的途径与能量代谢和FAO相关。具体地,FAO的主要调节物PPARα及其靶基因的肝表达在NASH中受到抑制。所述抑制在来自用甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸治疗的小鼠的肝中被逆转。
接着,我们应用基于体外萤光素酶的系统来测试甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸是否直接激活PPARα。
方法
COS-1和HepG2细胞获自美国典型培养物保藏中心(American Type CultureCollection)(ATCC),并在补加了10%胎牛血清(FBS,Sigma-Aldrich)和1%青霉素-链霉素(Pen-Strep,Gibco)的Dulbecco氏改良Eagle培养基(Dulbecco's Modified EagleMedium)(DMEM,Gibco)中于37℃和5%CO2培养。对于萤光素酶测定,将COS-1细胞接种在96-孔平板中。在60-70%汇合时,使用Lipofectamine 3000(Invitrogen)分别用PPREx3-TK-萤光素酶、PPARα和Renilla构建体以80ng、10ng和10ng进行转染。转染后24小时,将细胞血清饥饿(serum-starved)并用10μM PPARα激活物WY-14643(Cayman Chemicals,70730)、1mM甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸或10μM N-酰基氨基酸处理24小时(Cayman Chemicals,C20:4-Gly 90051,C18:1-Leu 20064)。使用双重萤光素酶报道基因测定系统(Dual-Luciferase Reporter Assay System)(Promega)评估萤光素酶活性,并通过Renilla进行归一化。
结果
尽管已知的PPARα激动剂WY-14643在10μM时显著增加了萤光素酶活性,但甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸在最多到1mM的浓度时均未显示出显著效果(图4A)。然后,我们测试了PPARα响应于N-酰基氨基酸的激活,所述N-酰基氨基酸被发现在来自喂食CD的小鼠或喂食NASH饮食并用甘氨酸或三肽甘氨酸-甘氨酸-亮氨酸治疗的那些小鼠的肝中更高(图1C-E)。与WY-14643类似,10μM的N-油酰基甘氨酸(C18:1-Gly)、N-花生四烯酰基甘氨酸(C20:4-Gly)或N-油酰基亮氨酸(C18:1-Leu)显著增加萤光素酶活性(图4B)。
在体内,N-酰基氨基酸的肝水平与关键PPARα靶基因的表达显著地且正相关,所述关键PPARα靶基因在调节线粒体生物发生和FAO中起主要作用,包括过氧化物酶体增殖激活受体,γ,辅激活物1α(Ppargc1a,图5A)、酰基辅酶A硫酯酶3(Acot3,图5B)和酰基辅酶A脱氢酶,长链(Acadl,图5C)。因此,N-酰基氨基酸在体外直接激活PPARα,并与其体内关键靶基因的表达有关。
实施例4
N-酰基氨基酸经由脂肪酸β氧化刺激脂质利用
为了评估N-酰基氨基酸经由FAO对脂质利用的直接作用,我们在HepG2细胞中应用了Seahorse测定。
方法
HepG2细胞获自美国典型培养物保藏中心(ATCC),并在补加了10%胎牛血清(FBS,Sigma-Aldrich)和1%青霉素-链霉素(Pen-Strep,Gibco)的Dulbecco氏改良Eagle培养基(DMEM,Gibco)中于37℃和5%CO2培养。使用Seahorse XFe96分析仪(Agilent)评估氧消耗率(OCR)和对FAO的依赖性。HepG2细胞以2.5x104个细胞/孔接种在XF96细胞培养微量培养板(Agilent)中。第二天,根据制造商的说明书对XFe96传感器筒进行水合。细胞(端口1)用N-酰基氨基酸(10μM)或媒介物(EtOH)、益托某西尔(Agilent,6μM,端口2)以及最后用鱼藤酮+抗霉素A(R/A,Agilent,端口3)处理。
对于TG生物合成和水解测定,将HepG2细胞接种在12-孔平板中。在60-70%汇合时,细胞在补加了0.1%BSA的无血清培养基中用N-酰基氨基酸(10μM)或媒介物(EtOH)处理,并于37℃用[3H]-乙酸盐(3.3μCi/ml,ART 0202,American Radiolabeled Chemicals)刺激3小时以评估TG生物合成速率。在一些孔中,细胞用PBS洗涤两次([3H]-乙酸盐撤回),并在补加了0.1%BSA的无血清培养基中与N-酰基氨基酸(10μM)或媒介物(EtOH)一起再温育3小时以评估TG水解速率。在上述温育时间段结束时,用PBS洗涤细胞两次。使用3:2比例(v:v)的己烷(≥99%,Sigma-Aldrich 32293)和异丙醇(≥99.5%,Fisher ScientificA426-4)提取细胞脂质,且使己烷相蒸发48小时。然后,在硅胶板(60F254,M1057150001,Fisher Scientific)上通过薄层层析(TLC)分离脂质,并在130:30:1.5比例(v:v:v)的己烷/乙醚(≥99.9%,309966,Sigma-Alrich)/乙酸(≥99.7%,A38-212,FisherScientific)中显象。TG点通过碘蒸气显示(使用适当的标准用于进行鉴定),且[3H]-标记通过Tri-Carb 2810TR液体闪烁分析仪(PerkinElmer)计数。将数据相对于蛋白水平归一化,并表示为每分钟计数(CPM)/mg细胞蛋白。
结果
用N-花生四烯酰基甘氨酸(C20:4-Gly)或N-油酰基亮氨酸(C18:1-Leu)的急性刺激显著增加了细胞的氧消耗率(OCR),这通过使用肉碱棕榈酰转移酶-1(CPT-1)的抑制剂益托某西尔阻断FAO来减弱,所述益托某西尔是调节脂肪酸的线粒体摄取及其后来的β-氧化的必需步骤的关键参与者(player)(图6A,B)。然后,我们通过监控[3H]-标记的乙酸盐在有或没有N-酰基氨基酸的情况下向TG中的并入来评估脂质生物合成及其水解的速率。N-花生四烯酰基甘氨酸(C20:4-Gly)和N-油酰基亮氨酸(C18:1-Leu)均减弱了TG生物合成的速率,然而,只有N-花生四烯酰基甘氨酸(C20:4-Gly)显著加快了TG水解的速率(图6C,D)。这些结果表明,N-酰基氨基酸,特别是N-花生四烯酰基甘氨酸(C20:4-Gly),经由FAO直接刺激脂质利用,从而突出了它们对脂肪性肝炎、纤维化和CVD的治疗潜力。
实施例5
小鼠中NASH的治疗
图7显示了小鼠中NASH研究的实验设计。
方法
C57BL/6J小鼠被喂食标准饮食(SD)或非酒精性脂肪性肝炎(NASH)饮食16周。NASH确认后,将小鼠随机化以接受10mg/kg/d(I.P.)N-油酰基亮氨酸(C18:1-Leu)或等量的油酸(C18:1)或媒介物(EtOH)达在NASH饮食上的额外6周。对照小鼠喂食SD并施用媒介物。
结果
图8证实C18:1-Leu在不影响肥胖的情况下降低体重。
图9证实C18:1-Leu对NASH中的全身能量平衡没有显著影响。
图10证实C18:1-Leu显著降低肝肿大。
图11证实C18:1-Leu降低循环肝酶。
图12证实C18:1-Leu显著降低饮食诱导的NASH。
图13证实C18:1-Leu显著降低脂肪肝。
图14证实C18:1-Leu显著降低NASH饮食诱导的肝和全身炎症。
图15证实C18:1-Leu显著降低NASH饮食诱导的肝纤维化。
实施例6
小鼠中动脉粥样硬化的治疗
图16显示了小鼠中动脉粥样硬化研究的实验设计。
方法
载脂蛋白E-缺陷(Apoe-'-)小鼠被喂食西方饮食(Western diet)(WD)8周。将小鼠随机化以接受7.5mg/kg/d(I.P.)N-油酰基亮氨酸(C18:1-Leu)或等量的油酸(C18:1)达在WD上的额外4周(n=10)。
结果
图17证实C18:1-Leu治疗对动脉粥样硬化小鼠中的体重和血浆胆固醇没有显著影响。
图18证实C18:1-Leu显著降低动脉粥样硬化斑块面积。
图19证实C18:1-Leu显著减少病变巨噬细胞。
虽然已经根据各种实施方案和实施例描述了本发明,但是应当理解,本领域的技术人员将想到变化和改进。因此,仅应对本发明施加如权利要求中出现的限制。
本申请中引用的所有文件均整体引入本文作为参考,其中特别注意对它们所提及的内容。
序列表
<110> 密歇根大学董事会
<120> N-酰基氨基酸产物及用途
<130> 30275/55769A/PC
<150> 63/067,175
<151> 2020-08-18
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Claims (52)
1.治疗主体中的心血管疾病状况的方法,其包括将药学上有效量的至少一种N-酰基氨基酸产物施用于所述主体,其中所述N-酰基氨基酸产物具有脂肪酸组分和氨基酸组分。
2.根据权利要求1所述的方法,其中所述脂肪酸组分是多不饱和脂肪酸或硝基脂肪酸。
3.根据权利要求2所述的方法,其中所述脂肪酸组分是ω3脂肪酸。
4.根据权利要求2所述的方法,其中所述脂肪酸组分是ω3脂肪酸的代谢物。
5.根据权利要求1所述的方法,其中所述氨基酸组分是甘氨酸、亮氨酸或D-亮氨酸。
6.根据权利要求1所述的方法,其中所述氨基酸组分是肽。
7.根据权利要求6所述的方法,其中所述氨基酸组分是甘氨酸-甘氨酸-亮氨酸或甘氨酸-甘氨酸-D-亮氨酸。
8.根据权利要求1所述的方法,其中施用至少N-花生四烯酰基甘氨酸或其药学上可接受的盐。
9.根据权利要求1所述的方法,其中施用至少N-油酰基亮氨酸或N-油酰基D-亮氨酸或其药学上可接受的盐。
10.根据权利要求1所述的方法,其中施用至少N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或N-油酰基甘氨酸-甘氨酸-D-亮氨酸,或其药学上可接受的盐。
11.根据权利要求1所述的方法,其中所述心血管疾病状况是冠心病、脑血管疾病、周围动脉疾病、风湿性心脏病、先天性心脏病、主动脉瘤和深静脉血栓形成和肺栓塞。
12.根据权利要求1所述的方法,其中所述治疗在所述主体中导致以下一种或多种:减少的动脉粥样硬化斑块、增加的心脏功能、减少的心肌肥大、降低的血压、减少的炎性状态和减小的主动脉直径。
13.根据权利要求1所述的方法,其中所述治疗缓和心力衰竭、代偿失调、心肌梗死和动脉瘤中的一种或多种。
14.治疗主体中的脂肪性肝炎的方法,其包括将药学上有效量的至少一种N-酰基氨基酸产物施用于所述主体,其中所述N-酰基氨基酸产物具有脂肪酸组分和氨基酸组分。
15.根据权利要求14所述的方法,其中所述脂肪酸组分是多不饱和脂肪酸或硝基脂肪酸。
16.根据权利要求15所述的方法,其中所述脂肪酸组分是ω3脂肪酸。
17.根据权利要求15所述的方法,其中所述脂肪酸组分是ω3脂肪酸的代谢物。
18.根据权利要求14所述的方法,其中所述氨基酸组分是甘氨酸、亮氨酸或D-亮氨酸。
19.根据权利要求14所述的方法,其中所述氨基酸组分是肽。
20.根据权利要求19所述的方法,其中所述氨基酸组分是甘氨酸-甘氨酸-亮氨酸或甘氨酸-甘氨酸-D-亮氨酸。
21.根据权利要求14所述的方法,其中施用至少N-花生四烯酰基甘氨酸或其药学上可接受的盐。
22.根据权利要求14所述的方法,其中施用至少N-油酰基亮氨酸或N-油酰基D-亮氨酸或其药学上可接受的盐。
23.根据权利要求14所述的方法,其中施用至少N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或N-油酰基甘氨酸-甘氨酸-D-亮氨酸,或其药学上可接受的盐。
24.根据权利要求14所述的方法,其中所述脂肪性肝炎是非酒精性脂肪性肝炎、酒精性肝病或酒精性脂肪性肝炎。
25.根据权利要求14所述的方法,其中所述治疗在所述主体中导致减少的肝脂肪、减少的炎性状态、减少的受损的肝细胞和减少的动脉粥样硬化斑块。
26.根据权利要求14所述的方法,其中所述治疗缓和肝硬化和肝细胞癌中的一种或多种。
27.治疗主体中的纤维化的方法,其包括将药学上有效量的N-酰基氨基酸产物施用于所述主体,其中所述N-酰基氨基酸产物具有脂肪酸组分和氨基酸组分。
28.根据权利要求27所述的方法,其中所述脂肪酸组分是多不饱和脂肪酸或硝基脂肪酸。
29.根据权利要求28所述的方法,其中所述脂肪酸组分是ω3脂肪酸。
30.根据权利要求28所述的方法,其中所述脂肪酸组分是ω3脂肪酸的代谢物。
31.根据权利要求27所述的方法,其中所述氨基酸组分是甘氨酸、亮氨酸或D-亮氨酸。
32.根据权利要求27所述的方法,其中所述氨基酸组分是肽。
33.根据权利要求32所述的方法,其中所述氨基酸组分是甘氨酸-甘氨酸-亮氨酸或甘氨酸-甘氨酸-D-亮氨酸。
34.根据权利要求27所述的方法,其中施用至少N-花生四烯酰基甘氨酸或其药学上可接受的盐。
35.根据权利要求27所述的方法,其中施用至少N-油酰基亮氨酸或N-油酰基D-亮氨酸或其药学上可接受的盐。
36.根据权利要求27所述的方法,其中施用至少N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或N-油酰基甘氨酸-甘氨酸-D-亮氨酸,或其药学上可接受的盐。
37.根据权利要求27所述的方法,其中所述治疗在所述主体中导致肝、心、肺、肾、皮肤或脂肪组织中胶原蛋白的减少。
38.根据权利要求27所述的方法,其中所述治疗在所述主体中导致胆管或胆囊中胶原蛋白的减少。
39.药物组合物,其包含(a)赋形剂和(b)N-花生四烯酰基甘氨酸或其药学上可接受的盐。
40.药物组合物,其包含(a)赋形剂和(b)N-油酰基亮氨酸或其药学上可接受的盐。
41.药物组合物,其包含(a)赋形剂和(b)N-油酰基D-亮氨酸或其药学上可接受的盐。
42.药物组合物,其包含(a)赋形剂和(b)N-花生四烯酰基甘氨酸、N-油酰基亮氨酸和N-油酰基D-亮氨酸的一种或多种或其药学上可接受的盐。
43.药物组合物,其包含(a)赋形剂和(b)N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸或其药学上可接受的盐。
44.药物组合物,其包含(a)赋形剂和(b)N-油酰基甘氨酸-甘氨酸-亮氨酸或其药学上可接受的盐。
45.药物组合物,其包含(a)赋形剂和(b)N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或其药学上可接受的盐。
46.药物组合物,其包含(a)赋形剂和(b)N-油酰基甘氨酸-甘氨酸-D-亮氨酸或其药学上可接受的盐。
47.药物组合物,其包含(a)赋形剂和(b)花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或N-油酰基甘氨酸-甘氨酸-D-亮氨酸中的至少两种或其药学上可接受的盐。
48.药物组合物,其包含(a)赋形剂和(b)N-花生四烯酰基甘氨酸、N-油酰基亮氨酸、N-油酰基D-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-亮氨酸、N-油酰基甘氨酸-甘氨酸-亮氨酸、N-花生四烯酰基甘氨酸-甘氨酸-D-亮氨酸或N-油酰基甘氨酸-甘氨酸-D-亮氨酸中的至少两种或其药学上可接受的盐。
49.诊断主体中的疾病状况的方法,其包括检测所述主体中的至少一种N-酰基氨基酸,
其中所述N-酰基氨基酸是N-花生四烯酰基甘氨酸、N-油酰基亮氨酸和N-油酰基D-亮氨酸中的至少一种,并且
其中所述N-酰基氨基酸的水平与所述疾病状况呈负相关。
50.根据权利要求49所述的方法,其中所述疾病状况是心血管疾病状况。
51.根据权利要求49所述的方法,其中所述疾病状况是脂肪性肝炎。
52.根据权利要求49所述的方法,其中所述疾病状况是纤维化。
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