CN115843267A - 呼吸道病毒感染的治疗 - Google Patents
呼吸道病毒感染的治疗 Download PDFInfo
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- CN115843267A CN115843267A CN202180034994.7A CN202180034994A CN115843267A CN 115843267 A CN115843267 A CN 115843267A CN 202180034994 A CN202180034994 A CN 202180034994A CN 115843267 A CN115843267 A CN 115843267A
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Abstract
本发明涉及呼吸道病毒感染(包括由冠状病毒引起的那些)的治疗。
Description
本发明涉及呼吸道病毒感染(包括由冠状病毒引起的那些)的治疗。
2020年春天,世界正处于Covid-19感染之中,有超过3百万确证病例和200,000例死亡。
存在有大量的处于测试中的潜在药品,在过去为其他感染所开发的那些和特异性地靶向SARS-CoV-2(引起Covid-19疾病的冠状病毒)的那些。自从一种感染性肺病被认定为一种新型疾病,现在大约四个月了。在于2019年12月31日给世界卫生组织的报告之后,在2020年1月11日,发表了SARS-CoV-2病毒的分子结构,从而起始了用于发现治疗和疫苗接种两者的世界范围的巨大努力。
直至此刻,还未出现有希望的治疗,几种治疗在令人失望的试验结果之后已被取消。全世界数十亿人处在封城(旨在减慢感染散播的措施)之下,公众和大多数医疗机构的期望和希望是:达到群体免疫所需要的人群百分比将会在接下来的几年中得到疫苗接种。同时,还将会有数百万人死亡,并且更多人将会罹患该疾病和遭受该大流行病带给世界经济的经济后果。
对于治疗的研究的主要焦点在于29个经鉴定的SARS-CoV-2蛋白质中的一些的分子细节和生物学功能。主要策略是在病毒进入细胞、复制和新形成的病毒脱落的这些所鉴定出的步骤中的任何一个处破坏病毒复制过程。
同时,基于现有药品已经或正在进行许多临床试验,希望为那些严重患病或死亡的患者找到更快的帮助。
根据本发明,提供了一种新的策略,其基于在新的病毒颗粒产生和脱落之前快速杀伤受感染细胞。对于受感染细胞的攻击的选择性不是基于病毒的分子结构,而是基于受感染细胞的细胞代谢过程的根本变化。任何病毒感染的主要特征是细胞合成途径被募集朝向病毒蛋白质和核酸的复制,从而导致增强的与环境的交换,包括增加的对于氨基酸的需求。在产生病毒蛋白质的同时,细胞仍然需要支持其自身对于蛋白质维持的需要。在那种代谢状态下,耗竭一种或多种氨基酸可以导致细胞的快速死亡并且因此阻止它散播感染。与此相反,健康细胞配备有控制穿过膜的大规模转运和来自蛋白质转换的氨基酸内部再循环的机制,其对于使得细胞从细胞外氨基酸耗竭中存活数天或甚至数周来说是足够有效的。
氨基酸耗竭已经在肿瘤学中在临床上使用了数十年(Garcia-Bermudez J,Williams RT,Guarecuco R,Birsoy K.Targeting extracellular nutrientdependencies of cancer cells.Mol Metab.2020,33:67-82)。迄今为止最成功的是在治疗血液癌中使用天冬酰胺酶,特别是在儿童急性淋巴细胞白血病中。此外,精氨酸的耗竭也吸引了很多兴趣,并且存在众多用精氨酸降解酶例如精氨酸酶和精氨酸脱亚胺酶的临床试验。
本发明的第一个方面为包含至少一种氨基酸降解酶的药物,其用于在用于治疗呼吸道的病毒感染的方法中使用。
本发明的一个进一步的方面为用于治疗呼吸道的病毒感染的方法,其包括向有此需要的受试者施用治疗有效量的包含至少一种氨基酸降解酶的药物。
所述药物适合于在兽医学中使用,和特别地适合于在人类医学中使用。
在某些实施方案中,所述病毒感染为冠状病毒感染,例如被SARS-CoV-1、SARS-CoV-2或MERS-CoV或者与普通感冒相关联的冠状病毒(例如乙型冠状病毒(Betacoronavirus)1,例如毒株OC43、毒株229E、毒株NL63或毒株HKU1或者任何其他毒株)感染。在特别的实施方案中,所述病毒感染为被SARS-CoV-2感染。
在进一步的实施方案中,所述病毒感染为流感病毒感染。存在有三个主要的流感病毒群:甲、乙和丙型。最常见的是甲型流感病毒,其再细分为在血清学上不同的类型,例如H1N1、H2N2、H3N2等。野生水禽是许多甲型流感病毒变种的宿主。典型的季节性流感最常见地为H1N1和H3N2型。1918年的最大的流感大流行病由H1N1型病毒引起。乙型流感病毒几乎仅在人类中发现,而丙型流感病毒感染人、狗和猪。虽然这些病毒的大多数也经由呼吸道传播,但是它们倾向于全身性地快速散布,并且在经过感染的非常早期阶段,可能需要全身治疗。
向罹患由呼吸道的病毒感染引起的、与之相关联的和/或与之相伴随的疾病的受试者(特别是人受试者)施用所述药物。在某些实施方案中,所述受试者罹患由呼吸道的冠状病毒感染引起的、与之相关联的和/或与之相伴随的疾病。在某些实施方案中,所述疾病为SARS、Covid-19、MERS或普通感冒。
所有蛋白质都由20种氨基酸构成:天冬氨酸(Asp);谷氨酸(Glu);精氨酸(Arg);赖氨酸(Lys);组氨酸(His);天冬酰胺(Asn);谷氨酰胺(Gln);丝氨酸(Ser);苏氨酸(Thr);酪氨酸(Tyr);丙氨酸(Ala);甘氨酸(Gly);缬氨酸(Val);亮氨酸(Leu);异亮氨酸(Ile);脯氨酸(Pro);苯丙氨酸(Phe);甲硫氨酸(Met);色氨酸(Trp);和半胱氨酸(Cys)。在这二十种之中,九种氨基酸是必需的(Lys、His、Thr、Val、Leu、Ile、Phe、Met和Trp),即它们无法由哺乳动物合成。Arg是半必需的,即一些合成是可能的但是对于有规律的需求来说是不足的。
根据本发明,所述氨基酸降解酶为能够降解上面所明确说明的氨基酸中的一种或多种氨基酸的酶。存在有特异于这些氨基酸的降解的酶;对于它们中的一些,已知多种降解途径。为了杀伤被病毒(例如SARS-CoV-2)感染的细胞,任何降解酶或者任何包含至少两种降解酶的组合是合适的。
在某些实施方案中,所述氨基酸降解酶为天冬酰胺降解酶,例如天冬酰胺酶(EC3.5.1.1)。所述天冬酰胺酶可以为任何可得的天冬酰胺酶,例如在细菌细胞例如大肠杆菌(Escherichia coli)或达当氏迪基氏菌(Dickeya dadantii)中产生的天冬酰胺酶,包括重组的天冬酰胺酶。在某些实施方案中,所述药物可以包含以解离形式(特别地以单体形式)的天冬酰胺酶,例如作为包含尿素的水性制备物,特别地以大约3mol/l至大约8mol/l的浓度,更特别地以大约4mol/l至大约6mol/l的浓度,例如大约5mol/l,如在共同拥有的申请EP19 178 062.6中所描述的,该申请的内容通过提及而合并入本文。
在某些实施方案中,所述氨基酸降解酶为精氨酸降解酶,例如精氨酸脱亚胺酶(EC3.5.3.6),精氨酸酶(EC 3.5.3.1),例如I型精氨酸酶或II型精氨酸酶,和精氨酸脱羧酶(EC4.1.1.19),例如I型精氨酸脱羧酶或II型精氨酸脱羧酶。在所述两种类型的精氨酸脱羧酶(生物合成的和生物降解的)之中,后者具有更有利的动力学参数,其待用于在人和动物中的精氨酸耗竭。
在某些实施方案中,所述氨基酸降解酶为甲硫氨酸降解酶,例如甲硫氨酸酶(EC4.4.1.11)。
在某些实施方案中,所述氨基酸降解酶为色氨酸降解酶,例如色氨酸侧链氧化酶(EC 1.13.99.3),例如I型色氨酸侧链氧化酶和II型色氨酸侧链氧化酶。
在某些实施方案中,所述药物包含两种或更多种(例如三种或四种)选自下列的氨基酸降解酶的组合:(i)天冬酰胺降解酶,例如天冬酰胺酶(EC 3.5.1.1);(ii)精氨酸降解酶,例如精氨酸脱亚胺酶(EC3.5.3.6),精氨酸酶(EC 3.5.3.1),例如I型精氨酸酶或II型精氨酸酶,和精氨酸脱羧酶(EC 4.1.1.19);(iii)甲硫氨酸降解酶,例如甲硫氨酸酶(EC4.4.1.11);和/或(iv)色氨酸降解酶,例如色氨酸侧链氧化酶(EC 1.13.99.3),例如I型色氨酸侧链氧化酶和II型色氨酸侧链氧化酶。
在特别的实施方案中,所述药物进一步包含胰岛素。所述胰岛素可以是任何类型的胰岛素,例如人胰岛素,动物胰岛素,胰岛素类似物,包括具有短的半寿期和具有长的半寿期的胰岛素类似物,或促胰岛素肽。优选的胰岛素具有短的半寿期,例如大约12小时或更短,大约8小时或更短,或者大约4小时或更短的半寿期,例如来自Novo Nordisk的所述药物可以为包含酶和胰岛素的混合物的单一组合物,或者几种组合物的组合,其中一种组合物包含酶,而另一种组合物包含胰岛素。
在某些实施方案中,所述药物局部地进行施用,例如以口服方式或以鼻方式,特别是通过吸入,由此可以避免在体液中被稀释。例如,用于吸入的单剂量总体积可以为大约1ml至大约4ml,优选地大约2ml至大约2.5ml。经烟雾化的酶溶液的几分钟的吸入可以递送有效剂量。例如,所述药物可以施用至上气道例如口腔、鼻腔、鼻旁窦、咽和/或喉,和/或下气道例如支气管和/或肺。
在某些实施方案中,所述药物全身地进行施用,特别是在已散布到整个受试者身体的晚期阶段病毒感染中。在这样的情况下,所述药物也可以全身地进行递送,例如通过静脉内输注或肌内注射,如在肿瘤学中所实践的。
所述药物可以以任何合适的剂型施用给患者,例如,作为冲洗溶液、喷雾剂或气雾剂,或者作为可注射或可注入的制备物。典型地,所述药物作为包含活性试剂和在药学上可接受的载体或赋形剂的药学组合物来进行施用。合适的载体和赋形剂的例子是熟练的开业医生所熟知的。
在某些实施方案中,所述药物在早期感染阶段中进行施用,例如在其中上气道例如口腔、鼻腔、鼻旁窦、咽和/或喉被感染,而下气道例如支气管和/或肺未被感染的感染阶段中。在进一步的实施方案中,所述化合物在其中下气道例如支气管和/或肺被感染的晚期感染阶段中进行施用。进一步地,所述化合物可以在其中受试者罹患呼吸功能障碍和任选地施行通气的感染阶段中进行施用。
所述药物以治疗有效量进行施用。像大多数其他呼吸道病毒一样,SARS-CoV-2主要(可能专门)感染呼吸道的衬细胞。肺泡的总表面积为大约70m2。被包含肺表面活性剂的液体覆盖的单细胞层将空气与在肺泡背侧上的毛细血管分开。如果液体层为1微米厚,那么待递送酶所采取的体积为大约10至100ml。体外实验已显示,在生长培养基中的处于10个单位/ml的氨基酸降解酶在杀伤癌细胞而非健康细胞方面已经是有效的。因此,在某些实施方案中,特别是对于局部递送,所述药物以大约100至大约10,000个单位的酶,特别是大约500至大约2000个单位的酶/应用的量进行施用。
对于全身递送,所述酶可以以高得多的剂量进行施用。待向有此需要的人受试者进行施用的剂量典型地将会在大约250至大约2,500个单位的酶/kg体重/天的范围中,取决于受试者以及待治疗的病症的类型和严重度。典型地,待向人患者进行施用的剂量将会为大约1,200个单位/kg/天。
胰岛素可以以治疗有效量与酶分开地或相混合地进行共施用。对于局部递送,胰岛素可以以例如大约10至大约500个单位的胰岛素,特别是大约50至大约100个单位的胰岛素/应用的量进行施用。对于全身递送,胰岛素可以以例如大约50至大约750个单位的胰岛素,特别是大约250至大约500个单位的胰岛素/天的更高量进行施用。吸入(例如作为干粉末)是一种优选的递送途径,但是通过静脉内输注或肌内注射进行施用也是可能的。当共施用胰岛素时,应当监测葡萄糖水平,例如在施用后几小时,并且进行纠正,如果需要。
取决于感染的阶段和严重度,所述药物可以在感染过程中施用一次或几次。例如,所述化合物可以一周一次,每第二天,每天一次,或每天几次(例如2或3次)进行施用。
所述药物可以单独地或者与另一种活性试剂一起进行施用。所述另一种活性试剂可以选自:抗病毒试剂例如瑞德西韦、利托那韦和/或洛匹那韦,和/或干扰素-β,或针对冠状病毒抗原的抗体。
根据一个特别优选的实施方案,施用天冬酰胺酶和胰岛素(例如具有短的半寿期的胰岛素)的组合,例如作为经烟雾化的混合物。由于在本申请中的主要靶标仅是在肺中的衬细胞层,因此小体积(例如0.5至1.0ml)的胰岛素(其例如包含大约100个单位/ml)以及与之相混合的大约相同体积的天冬酰胺酶(其例如包含大约2,000个单位/ml)提供了基础剂量,其可以作为气雾剂来进行递送,通过吸入几分钟,和然后在几个小时后进行重复(如果需要)。
Claims (15)
1.包含至少一种氨基酸降解酶的药物,其用于在用于治疗呼吸道的病毒感染的方法中使用。
2.权利要求1的药物,其中所述病毒感染为冠状病毒感染。
3.权利要求1或2的药物,其中所述病毒感染为被SARS-CoV-1、SARS-CoV-2或MERS-CoV或者与普通感冒相关联的冠状病毒感染,特别是被SARS-CoV-2感染。
4.权利要求1的药物,其中所述病毒感染为流感病毒感染。
5.前述权利要求中任一项的药物,其另外还包含胰岛素。
6.权利要求5的药物,其中所述酶和胰岛素作为单一组合物进行施用。
7.权利要求5的药物,其中所述酶和胰岛素作为分开的组合物进行施用。
8.前述权利要求中任一项的药物,其局部地进行施用,例如通过吸入,或者全身地进行施用。
9.权利要求8的药物,其中用于吸入的单剂量体积为大约1ml至大约4ml,优选地大约2至大约2.5ml。
10.前述权利要求中任一项的药物,其中所述酶选自由下列各项组成的组:(i)天冬酰胺酶,(ii)精氨酸酶、精氨酸脱亚胺酶或精氨酸脱羧酶,(iii)甲硫氨酸酶,和(iv)色氨酸侧链氧化酶,或者其任何组合。
11.前述权利要求中任一项的药物,其包含:对于局部施用,大约500至大约2000个单位的酶/应用的剂量;或者对于全身施用,大约250至大约2,500个单位的酶/kg体重/天的剂量。
12.权利要求5、6或7的药物,其包含:对于局部施用,大约50至大约100个单位的胰岛素/应用的剂量;或者对于全身施用,大约250至大约500个单位的胰岛素/天的剂量。
13.前述权利要求中任一项的药物,其包含天冬酰胺酶和胰岛素,特别是天冬酰胺酶和胰岛素的混合物,用于通过吸入施用。
14.前述权利要求中任一项的药物,其包含以解离形式的天冬酰胺酶,特别地在包含尿素的制备物中,和任选地胰岛素。
15.用于治疗呼吸道的病毒感染的方法,其包括向有此需要的受试者施用治疗有效量的包含至少一种氨基酸降解酶的药物。
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EP20174730 | 2020-05-14 | ||
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PCT/EP2021/062513 WO2021228875A1 (en) | 2020-05-14 | 2021-05-11 | Treatment of respiratory viral infections |
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EP (1) | EP4149619A1 (zh) |
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- 2021-05-11 US US17/924,905 patent/US20230181694A1/en active Pending
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