Oleandrin

▎药明康德内容团队编辑 在很多地方，尤其是南方城市，夹竹桃是很常见的绿化树种。四季常绿，叶子略似竹叶，花朵形似桃花。耐寒、防尘、抗污染，又长得美，让夹竹桃被广为栽培，用于美化环境。但夹竹桃有一个“致命”的问题——字面意义的“致命”：全株有毒。时有新闻报道，动物或人因误食夹竹桃的叶或汁液而中毒，引起呕吐、皮肤发炎甚至死亡。不少文艺作品里也提到过夹竹桃的毒力。比如《甄嬛传》里就有用夹竹桃投毒的桥段。夹竹桃的表皮、汁液含有多种有毒物质，其中最主要的剧毒成分叫做欧夹竹桃苷（oleandrin）。欧夹竹桃苷属于一类强心苷类化合物，会作用于人的消化系统系统、心脏和中枢神经，对人类的致死量约为0.3 mg/kg，有人计算过几片夹竹桃叶子就足以让一个成人死于心脏功能衰竭。这样一种剧毒化合物，让人唯恐避之不及，但毒物在合适的剂量下也可以变成良药。在一项新发表在《自然-通讯》（Nature Communications）的研究中，科研人员运用人工智能（AI）的强大筛选能力，发现欧夹竹桃苷有望开发为一种强大的抗衰老药物（senolytics）。抗衰老药物，顾名思义是用于清除衰老细胞。已有的研究表明，老年个体中，衰老细胞不能被有效清除是一个重要的致病机制。当细胞进入衰老状态，不能继续分裂增殖，也不甘心死亡，而是持续分泌炎性分子，影响邻近细胞，损伤组织功能。衰老细胞数量持续增加，与一系列疾病有关，包括2型糖尿病、肺纤维化、骨关节炎、神经变性等等。因此，很多研究正在寻找的抗衰老药物，就是希望特异性靶向衰老细胞将其消除，同时不影响健康细胞，从而减缓衰老和预防年龄相关疾病。基于这一策略，目前已有零星几种化合物在临床试验中显示出疗效，例如达沙替尼和槲皮素。然而面对抗衰的广泛需求，可选药物的种类还是太少了。图片来源：123RF为了加快抗衰老药物的发现过程，一些新研究开始借助发展迅猛的人工智能，训练机器学习模型识别出新的候选抗衰老药物。在此次研究中，来自英国爱丁堡大学和西班牙坎塔布里亚大学的科研人员为AI模型提供了已知senolytics和非senolytics的示例，训练这些模型学会区分两者，然后用训练成绩最好的模型预测其他未见过的分子是否有作为抗衰老药物的潜力。在筛选了多个化合物文库后，AI模型用短短5分钟从4300多个分子中挑选出了21个得分最高的候选分子。随后，研究人员在衰老细胞和健康细胞上对选出的候选分子进行了测试。▲在癌基因诱导的衰老细胞中进一步筛选，21种化合物中有3种显示出抗衰老活性（图片来源：参考资料[1]）来自夹竹桃的欧夹竹桃苷以及另外两种来自植物的天然分子——periplocin（来自杠柳）与ginkgetin（来自银杏）——脱颖而出。细胞实验表明，它们能够消除衰老细胞，同时保持大多数正常细胞存活。欧夹竹桃苷的表现尤其瞩目，进一步生物学实验表明，它比强心苷类药物中表现最好的已知抗衰老药物效力更强，在极低的纳摩尔范围下选择性清除衰老细胞，且不影响正常细胞的增殖能力和活力。“至关重要的是，”研究人员在论文中指出，“我们的方法将用于实验筛选的化合物数量减少至不足原来的1/200，从而大大提高了效率。”研究团队表示，他们下一步计划通过人肺组织、实验动物等测试欧夹竹桃苷等候选抗衰老分子，并寻找局部施药的方法以便克服全身毒性问题。未来研究团队还将借助AI探索更多可能的潜在疗法，训练它们发现更多候选抗衰疗法。参考资料：[1] Vanessa Smer-Barreto et al, Discovery of senolytics using machine learning, Nature Communications (2023). DOI: 10.1038/s41467-023-39120-1[2] AI finds drugs that could fight aging and age-related diseases. Retrieved July 11, 2023 from https://medicalxpress.com/news/2023-07-ai-drugs-aging-age-related-diseases.html本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

March 17, 2021 10:00 UTC SAN ANTONIO--(BUSINESS WIRE)-- An article published last week in the Journal of Biomedicine & Pharmacotherapy ( ; Vol 138 (2021) 111457) presents in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (developed by Phoenix Biotechnology, Inc. and designated as PBI-06150), as well as in vivo evidence of the safety and efficacy of PBI-06150. This press release features multimedia. View the full release here: The Journal of Biomedicine & Pharmacotherapy is an open access, peer-reviewed medical journal covering medical applications of pharmacology. It was established in 1956 and is published 10 times a year. The authors of the article titled “Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2” state, “The potent prophylactic and therapeutic antiviral activities demonstrated here, together with initial evidence of its safety and efficacy in a relevant hamster model of COVID-19, support the further development of oleandrin and/or defined extracts containing this molecule for the treatment of SARS-CoV-2 and associated COVID-19 disease and potentially also for reduction of virus spread by persons diagnosed early after infection.” They further state, “With continued expansion of the coronavirus (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease . . . Moreover, it is possible that vaccines may require continuous development due to the ongoing mutation of coronavirus into different variants . . . Furthermore, except for Remdesivir, many of the existing antiviral drugs tested to date have shown limited or no efficacy in clinical trials. Thus, identification of safe and effective therapeutic agents that can be effective against SARS-CoV-2 remains an unmet need.” The article is a collaborative effort which covers the results of two separate studies of the impact of oleandrin and PBI-06150 on SARS-CoV-2. The in vitro study was conducted by scientists at the University of Texas Medical Branch (UTMB) in Galveston, while researchers at Texas Biomedical Research Institute (Texas Biomed) in San Antonio conducted the in vivo study, utilizing golden Syrian hamsters. Both studies were sponsored by Phoenix Biotechnology ( ). The in vitro study, using Vero cells, found that “prophylactic (pre-infection) oleandrin (as either the pure compound or as the active principal ingredient in PBI-06150) administration at concentrations as low as 0.05 μg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 μg/ml concentration resulted in a greater than 3000-fold reduction in infectious virus production. The half maximal effective concentration (EC50) values were 11.98 ng/ml when virus output was measured at 24 hours post-infection, and 7.07 ng/ml measured at 48 hours post-infection.” “Therapeutic (post-infection) treatment up to 24 h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1 μg/ml and 0.05 μg/ml concentrations causing greater than 100-fold reduction as measured at 48 hours, and the 0.05 μg/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10 μg/ml were well tolerated in Vero cells.” In the in vivo study, the authors state, “We also present in vivo evidence of the safety and efficacy of defined N. oleander extract (PBI-06150), which was administered to golden Syrian hamsters in a preparation containing as high as 130 μg/ml of oleandrin. In comparison to administration of control vehicle, PBI-06150 provided a statistically significant reduction of the viral titer in the nasal turbinates (nasal conchae).” This journal article follows a November article in the Journal of Experimental Pharmacology which was titled “Antiviral Effects of Oleandrin” and reviewed a series of research studies which establish the antiviral activity of oleandrin, in particular oleandrin’s strong antiviral activity against “enveloped” viruses and its ability to inhibit production of infectious virus particles when used for treatment prior to, as well as after, infection of SARS-CoV-2. That article states, “The ability of oleandrin to inhibit the relative infectivity of progeny virus particles may offer a unique approach to treating certain viral diseases.” It further stated “The therapeutic potential of oleandrin and extracts containing this unique molecule against a wide variety of ‘enveloped’ viruses is evident from the preclinical studies reviewed in this article . . . The speed of development and international spread of viruses such as SARS-CoV-2 necessitates consideration of a new strategy against these viruses . . . Having a compound or plant extract with significant demonstrated potential to prevent as well as treat a wide variety of viruses deserves serious consideration.” About Phoenix Biotechnology, Inc. Phoenix Biotechnology, Inc., headquartered in San Antonio, has been exploring the health-related benefits of oleandrin, a novel extract of Nerium oleander for more than 20 years. Research was initiated at the University of Texas MD Anderson Cancer Center for the potential use of this extract against cancer. The company’s research led to the development of a proprietary supercritical CO2 extract of Nerium oleander into a new botanical drug – PBI-05204. Extensive research has also been undertaken to determine the efficacy of oleandrin/PBI-05204 as a therapy for neurodegenerative disease as well as viral infections. One of the profound discoveries of the research program is that a key component of this PBI product crosses the blood brain barrier, opening up the possibility of treatment in the areas of cancer, neurodegenerative diseases and as an antiviral product not currently available from any other known drug. PBI-05204 has been granted an IND through initial FDA review for Phase I and Phase II clinical oncology trials which were conducted in the United States. These trials have shown that this oral formulation is safe for administration to patients without severe toxicity or adverse effects. In response to the COVID-19 pandemic, the company focused research in 2020 on a potential treatment for this coronavirus. This effort resulted in two submissions to the FDA, one for a nutraceutical and the second for a pharmaceutical product. Preliminary discussions with the FDA have resulted in the request for additional studies to explore both efficacy and safety. These required trials should be completed within the next several months and, assuming the results are positive, we will pursue new applications for both products. View source version on businesswire.com: Contacts news@phoenixbiotechnology.com Source: Phoenix Biotechnology, Inc. Smart Multimedia Gallery Document Biomedicine & Pharmacotherapy Article: "Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2" Logo View this news release online at: