专访清华大学程功教授:受糖尿病患者易感新冠启发,发现广谱抗新冠代谢物

2022-05-11 网络 网络

《生物世界》第一时间专访了程功教授,通过此次专访,我们一起来了解这一发现历程及 1,5-AG 的潜在应用和价值。

2022年5月9日,清华大学医学院程功团队与合作者在 Nature Metabolism 期刊发表论文,筛选到一种结构与葡萄糖相似的人体小分子代谢物1,5-脱水山梨醇(1,5-AG),其可以显着抑制新冠病毒及其他冠状病毒感染。该研究揭示了糖尿病患者缺乏 1,5-AG 可能是其感染新冠后易发展危重症或死亡的重要因素。

《生物世界》第一时间专访了程功教授,通过此次专访,我们一起来了解这一发现历程及 1,5-AG 的潜在应用和价值。

病毒感染和感染后的疾病进展结果,是由复杂的宿主-病毒相互作用决定的。新型冠状病毒(SARS-CoV-2)是新冠肺炎(COVID-19)的病原体,在人类中呈现高度异质性的临床表现。大多数感染新冠病毒的人都表现出无症状或轻中度症状,然而,患有2型糖尿病等合并症的患者,感染后出现重症甚至死亡的风险则要高得多。说明糖尿病患者体内可能存在某些因素影响了其对新冠病毒的易感性。

尽管复杂的免疫学改变可能是这些人群脆弱性的基础,但代谢紊乱在糖尿病合并症患者中也很明显,这可能使他们易在病毒感染后发展为重症。但代谢因素在新冠肺炎(COVID-19)发病机制中的作用仍在很大程度上是未知的。

2022年5月9日,清华大学医学院程功团队与合作者在 Nature 子刊 Nature Metabolism 杂志发表题为:Aglucose-like metabolite deficient in diabetes inhibit cellular entry ofSARS-CoV-2(一种糖尿病相关的类葡萄糖代谢物抑制新冠病毒进入宿主细胞)的研究论文。

该研究筛选出一种结构与葡萄糖相似的人体小分子代谢物 1,5-脱水山梨醇(1,5-Anhydro-D-glucitol,1,5-AG),可以显着抑制新冠病毒感染,在人体中 1,5-AG 与血糖浓度严格负相关。

糖尿病患者体内 1,5-AG 显着缺乏,可能是导致糖尿病患者感染新冠病毒后易出现重症及死亡的重要原因。进一步研究显示,向糖尿病小鼠体内补充 1,5-AG 可有效阻抑新冠感染重症发病。

该研究发现并证实,与葡萄糖结构相似的人体小分子代谢物1,5-脱水山梨醇(1,5-Anhydro-D-glucitol,1,5-AG),能够与新冠病毒刺突蛋白的 S2 亚基结合,发挥有效的抗病毒作用,阻断刺突蛋白介导的病毒-宿主膜融合。

该研究还表明,糖尿病患者体内显着缺乏 1,5-AG,这可能是导致糖尿病患者感染新冠病毒后易出现重症及死亡的重要原因,由此揭示了 1,5-AG 介导的代谢稳态在 COVID-19 发病机制中的重要作用,并表明补充 1,5-AG 和改善糖尿病患者的高血糖可能有助于降低新冠发病率和/或预防重症新冠。

清华大学医学院程功教授、深圳市疾控中心张仁利教授、军事医学研究院赵光宇研究员及南方科技大学医学院李亮教授为本论文通讯作者。清华大学医学院2016级博士研究生童良琴,清华大学医学院肖小平博士,军事医学研究院李敏博士和深圳市疾控中心房师松博士为并列第一作者。

程功于2008年获得复旦大学微生物学博士学位,之后在美国耶鲁大学传染病系从事博士后研究工作,于2011年全职任教于清华大学,现为清华大学长聘教授、博士生导师,同时担任医学院副院长、党委副书记。

程功教授长期从事针对虫媒病毒性传染病的致病机理研究及疫苗研发,在国际主流期刊发表研究论文40余篇,系列研究成果为重要蚊媒病毒的防治提供了生物学基础,促进了烈性蚊媒病毒传染病知识概念体系的发展和完善,代表着我国在蚊媒病毒传染病这一生命医学热点领域的重要突破,并推动相关研究成果应用于新型药物及疫苗研发,为新发突发传染病防控、公共卫生安全提供了重要技术支撑,为有效防控传染病疫情做出突出贡献。

程功教授课题组

在这项研究中,程功团队等从人血清代谢物出发,评估人血清中的代谢物是否可能调节 新冠病毒感染。通过 3-kDa 过滤器离心分离人血清样品,然后将含有小分子代谢物的血清过滤液与 Vero 细胞一起孵育并进行新冠病毒感染实验。实验结果显示,与对照组相比,用血清过滤液处理的 Vero 细胞中新冠病毒病毒 RNA 量显着降低。

研究团队接下来的目标就是要从中人血清中鉴定出发挥抗病毒活性的代谢物,首先鉴定了298种小分子代谢物进行进一步研究(其中222种可商业购买)。使用每种代谢物分别与 Vero 细胞共培养,然后分别用新冠病毒感染。其中,有7种小分子代谢物对病毒的抑制率在95%以上,其中 N-oleoyl glycine 由于细胞毒性大而被排除。其余6种小分子代谢物中,1,5-AG、5-MT、CDCA 是可由人体细胞合成的内源性代谢物。

程功团队进一步检查了这些内源性代谢物的潜在作用,以研究宿主代谢与新冠病毒感染之间的相互作用。由于糖尿病是新冠重症的高危因素,研究团队调查了内源性代谢物水平是否与健康组和糖尿病组之间的不同抗病毒活性相关。

结果显示,1,5-AG(1,5-Anhydro-D-glucitol,1,5-脱水山梨醇)在正常人体血清中浓度为 100-300μM 并在各器官中呈稳态分布,而糖尿病患者体内 1,5-AG 的水平比健康人降低5-15倍。而 CDCA 和 5-MT 水平则不然。

程功教授表示,1,5-AG 是一种与糖尿病高度相关的代谢小分子,之前的研究显示,补充 1,5-AG 可能有利于抑制高血糖,改善代谢综合征。

接下来,研究团队发现,相比健康供者血清处理,用糖尿病患者血清处理的 Vero 细胞中新冠病毒 RNA 量显着更高。而在糖尿病患者血清中添加 1,5-AG 就可以显着减少新冠病毒 RNA 量。这表明 1,5-AG 具有显着的抗新冠病毒能力,进一步的支气管上皮类器官实验也证实了这一点。

通过对2型糖尿病db/db小鼠模型研究发现,糖尿病小鼠感染新冠病毒后体重下降明显,肺部病毒载量明显升高,肺部病理损伤严重,出现新冠感染重症表征。而给这些糖尿病小鼠补充 1,5-AG 后,可显着抑制新冠病毒感染,小鼠肺部病毒载量下降 100-1000 倍,大幅缓解肺部组织病变。

研究团队进行了进一步的机制研究,1,5-AG 可与新冠病毒刺突蛋白 S2 亚基 HR1 结构域的 V952 和 N955 位点结合,通过抑制 S2 亚基 6-HB 的形成,影响病毒-细胞膜融合的过程,从而抑制新冠病毒感染宿主细胞。

程功教授表示,对 1,5-AG 作用机制的研究显示,1,5-AG 的作用位点在冠状病毒中高度保守,因此,1,5-AG 不仅对 SARS-CoV-2 的各种突变株具有显著的抗病毒作用,还对 SARS-CoV 及 MERS-CoV 等致病性冠状病毒具有显著抗病毒作用,因此是一种可广泛抑制冠状病毒感染的人体代谢小分子。

1,5-AG影响糖尿病人对新冠病毒易感性示意图

程功教授告诉《生物世界》,除了上述细胞及小鼠模型实验外,团队还进一步综合了临床相关研究数据,发现重症新冠肺炎患者血清中 1,5-AG 的含量显着低于健康人和非重症新冠肺炎患者,这说明 1,5-AG 可影响人体对新冠病毒的易感性。这些发现不仅揭示了糖尿病患者感染新冠病毒后更易发展为重症的关键分子机制,还证实了补充 1,5-AG 有助于糖尿病患者抵抗新冠病毒感染。

1,5-AG 与血糖水平严格负相关,这是因为葡萄糖可以竞争性地和 1,5-AG 受体结合,从而影响肾小球对 1,5-AG 的重吸收,导致大量 1,5-AG 通过尿液被排出体外,使得体内 1,5-AG 的含量降低,这也是 1,5-AG 能作为监控糖尿病患者短期内血糖调控指标的原因。程功教授表示,目前课题组正在研究能否通过降糖药物处理的方法降低糖尿病小鼠的血糖水平,并联合口服 1,5-AG 来提高糖尿病小鼠体内 1,5-AG 的含量,从而影响新冠病毒感染。

众所周知,老年人易感新冠病毒且感染后更易发展为重症,之前的研究表明,1,5-AG 在老年人体内也显着下降,是人体衰老的生物标志物之一。因此,老年人 1,5-AG 水平降低与其感染新冠后重症率上升是否有关,值得进一步研究。

程功教授还表示,1,5-AG 广泛存在于我们日常食物中,比如在大豆中含量丰富。而且,1,5-AG 还是远志(Polygala tenuifolia)等多味中药的主要活性成分。基于这项研究成果,未来将有可能开发一种“药食同源”的营养策略来预防新冠感染引起的重症肺炎。

程功教授告诉《生物世界》,针对这项研究发现,课题组接下来将从两个方向推进后续研究。一是开发基于 1,5-AG 的缓释制剂。1,5-AG的优点在于它安全性和稳定性好,同时在肺泡灌洗液中浓度较高,若能显著提高 1,5-AG 血药浓度,可以有效抑制新冠病毒感染。但是由于它代谢较快,单次给药难以快速提高血药浓度。因此,想通过口服缓释制剂的方式,持续补充1,5-AG,达到显着提高其血药浓度的目的。二是对 1,5-AG 进行化学修饰和结构改造,从而在增强其与S2亚基亲和力的同时降低其代谢速率,更好地实现转化。

程功教授实验室在3月份发表了一篇预印本论文揭示了铁蛋白纳米颗粒的Omicron候选疫苗相对于传统疫苗和mRNA疫苗疫苗具有一些特点和优势。

程功教授课题组还一直致力于新型疫苗研发工作,在今年3月份,课题组在预印本 bioRxiv 发表了题为:Development of a ferritin-based nanoparticle vaccine against the SARS-CoV-2 Omicron variant 的论文,开发了针对新冠 Omicron 突变株的新型铁蛋白纳米颗粒候选疫苗。

程功教授表示,课题组在研的这一新型铁蛋白纳米颗粒疫苗,主要特点是引入“组装式”疫苗概念,通过二聚体及二十四聚体的级联放大作用,在疫苗的免疫原性及有效性上实现“1+1>2”的显着提升。从动物免疫结果来看,该纳米颗粒疫苗可诱导高滴度的 Omicron 特异性抗体, 与单独的 RBD 蛋白相比,免疫原性更强。在中和抗体方面,该纳米颗粒疫苗对相继出现的 Omicron 突变株的 BA.1 和 BA.2 亚型均显示出高水平的中和活性。

此外,针对新冠原始株、Alpha、Beta、Gamma、Detla 等流行株均具有较好的中和活性。与传统疫苗和 mRNA 疫苗相比,具有一定的优势:工艺成熟简单,易于生产;不涉及活病毒培养,安全性高;灵活性高,尤其针对 Omicron 流行株快速突变的特点,能够快速应对,短时间内制备疫苗,开展相关研究。

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#插入话题
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  3. [GetPortalCommentsPageByObjectIdResponse(id=1660026, encodeId=e1ae1660026ce, content=<a href='/topic/show?id=24e82545262' target=_blank style='color:#2F92EE;'>#代谢物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=25452, encryptionId=24e82545262, topicName=代谢物)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6c1225086772, createdName=旅苦化文_216, createdTime=Sat Mar 11 00:45:11 CST 2023, time=2023-03-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703367, encodeId=fc221e0336708, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Tue Nov 15 20:45:11 CST 2022, time=2022-11-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1219507, encodeId=640a121950e01, content=思路很重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6ca52621701, createdName=lywyz2, createdTime=Sat May 14 06:03:10 CST 2022, time=2022-05-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1475266, encodeId=935614e526605, content=<a href='/topic/show?id=935fe6718e3' target=_blank style='color:#2F92EE;'>#糖尿病患者#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76718, encryptionId=935fe6718e3, topicName=糖尿病患者)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a38f7243741, createdName=xue8604, createdTime=Thu May 12 03:45:11 CST 2022, time=2022-05-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1500177, encodeId=ede415001e7f4, content=<a href='/topic/show?id=9e6866216d7' target=_blank style='color:#2F92EE;'>#清华#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=66216, encryptionId=9e6866216d7, topicName=清华)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=10f29422809, createdName=医生2397, createdTime=Thu May 12 03:45:11 CST 2022, time=2022-05-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1218805, encodeId=cf67121880510, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8a455449587, createdName=无糖去冰, createdTime=Wed May 11 17:56:58 CST 2022, time=2022-05-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1218767, encodeId=9e491218e67f9, content=学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=101, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f03a5433387, createdName=ms5000000518166734, createdTime=Wed May 11 16:06:16 CST 2022, time=2022-05-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1218739, encodeId=7c5c1218e397a, content=坚持学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210313/9df56058b3964a8cac82563f95f0389d/c1b478592e8e4463bef44d32712e98fd.jpg, createdBy=ea905324251, createdName=杨海东, createdTime=Wed May 11 14:30:57 CST 2022, time=2022-05-11, status=1, ipAttribution=)]
    2022-05-14 lywyz2

    思路很重要

    0

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    2022-05-12 医生2397
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    2022-05-11 无糖去冰

    学习

    0

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    2022-05-11 ms5000000518166734

    学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习

    0

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    2022-05-11 杨海东

    坚持学习

    0

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