main protease

主要蛋白酶
  • 文章类型: Journal Article
    COVID-19大流行继续对全球健康构成威胁,并为研发有效的抗冠状病毒药物敲响警钟,这对患者至关重要,也是当前流行病和未来危机迫切需要的。主要蛋白酶(Mpro)是SARS-CoV-2成熟过程中必不可少的酶,在调节病毒RNA的复制和转录中起着不可替代的作用。由于其高保守性和人体中不存在同源蛋白酶,它已成为开发针对SARS-CoV-2的抗病毒剂的理想靶标。在SARS-CoV-2Mpro抑制剂中,非肽化合物由于其优异的抗病毒活性和改善的代谢稳定性而具有广阔的前景。在这次审查中,我们概述了2020年以来非肽类SARS-CoV-2MPro抑制剂的研究进展。这些努力深入研究了分子结构,结构-活动关系(SARs),生物活性,以及这些抑制剂与Mpro的结合模式。这篇综述旨在为抗SARS-CoV-2药物以及广谱冠状病毒Mpro抑制剂的开发提供有价值的线索和见解。
    The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (Mpro) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body. Among the SARS-CoV-2 Mpro inhibitors, non-peptidic compounds hold promising prospects owing to their excellent antiviral activity and improved metabolic stability. In this review, we offer an overview of research progress concerning non-peptidic SARS-CoV-2 Mpro inhibitors since 2020. The efforts delved into molecular structures, structure-activity relationships (SARs), biological activity, and binding modes of these inhibitors with Mpro. This review aims to provide valuable clues and insights for the development of anti-SARS-CoV-2 agents as well as broad-spectrum coronavirus Mpro inhibitors.
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  • 文章类型: Journal Article
    半胱氨酸蛋白酶涉及广泛的生物学功能,从细胞外基质周转到免疫。在几种疾病的发生和发展中起着重要作用,包括癌症,免疫相关和神经退行性疾病,病毒和寄生虫感染,半胱氨酸蛋白酶代表了开发治疗工具的有吸引力的药物靶标。
    综述了最近的科学和专利文献,重点研究了具有潜在治疗应用的半胱氨酸蛋白酶抑制剂的设计和研究。
    许多有效的结构多样的半胱氨酸蛋白酶抑制剂的发现为治疗工具的开发带来了新的挑战和机遇。一些蛋白酶的机制研究和X射线晶体结构的可用性,单独和与抑制剂复合,为合理设计和开发有效和选择性的半胱氨酸蛋白酶抑制剂作为治疗不同疾病的临床前候选药物提供重要信息。
    UNASSIGNED: Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools.
    UNASSIGNED: Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed.
    UNASSIGNED: The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.
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  • 文章类型: Journal Article
    2003年发现的严重急性呼吸道综合症相关冠状病毒(SARS-CoV)感染了26个国家的8000人,其中800人死亡,通过综合症监测和加强检疫,很快就得到了控制和根除。与SARS-CoV-2密切相关的冠状病毒是2019年发现的COVID-19的病原体,其传染性和灾难性性大大增强。它感染了超过200个国家的数十亿人,并引起了各种流感样症状,包括>600万人死于或感染病毒。尽管有几种针对SARS-CoV-2的疫苗和抗病毒药物,但由于病毒的进化和未来可能出现的冠状病毒,仍需要寻找新的治疗方法。这些冠状病毒的主要蛋白酶(Mpro)在其生命周期中起着重要作用,并且对于病毒复制至关重要。这篇文章是对功能的全面回顾,SARS-CoV和-CoV-2Mpro的结构和抑制作用,包括结构-活动关系,蛋白质-抑制剂相互作用和临床试验状态。
    Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) identified in 2003 infected ∼8000 people in 26 countries with 800 deaths, which was soon contained and eradicated by syndromic surveillance and enhanced quarantine. A closely related coronavirus SARS-CoV-2, the causative agent of COVID-19 identified in 2019, has been dramatically more contagious and catastrophic. It has infected and caused various flu-like symptoms of billions of people in >200 countries, including >6 million people died of or with the virus. Despite the availability of several vaccines and antiviral drugs against SARS-CoV-2, finding new therapeutics is needed because of viral evolution and a possible emerging coronavirus in the future. The main protease (Mpro) of these coronaviruses plays important roles in their life cycle and is essential for the viral replication. This article represents a comprehensive review of the function, structure and inhibition of SARS-CoV and -CoV-2 Mpro, including structure-activity relationships, protein-inhibitor interactions and clinical trial status.
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  • 文章类型: Journal Article
    未经批准:本文提供了与FDA批准的药物相关的最新文献,这些药物已被重新用作对抗COVID-19的潜在候选药物。此外,我们对经常研究的目标进行了高质量的药效团研究,即,主要的蛋白酶,RNA依赖性RNA聚合酶,和刺突蛋白。
    未经批准:自从COVID-19大流行以来,整个科学界仍然无法发明COVID-19的绝对治疗剂。考虑到这样一个事实,药物再利用策略似乎是开发新的治疗干预措施的真正可行的方法。
    UNASSIGNED:药物再利用探索了先前批准的已知安全性和药代动力学特征的药物,以获得可能的新作用,降低成本,时间,并预测预期的副作用和药物相互作用。COVID-19的毒力机制与其他病毒相似,使抗病毒药物广泛用于寻求治疗候选药物。我们的主要蛋白酶药效学研究揭示了多种特征,可能是即将进行的研究的起点。
    UNASSIGNED: This article provides a review of the recent literature related to the FDA-approved drugs that had been repurposed as potential drug candidates against COVID-19. Moreover, we performed a quality pharmacophore study for frequently studied targets, namely, the main protease, RNA-dependent RNA polymerase, and spike protein.
    UNASSIGNED: Ever since the COVID-19 pandemic, the whole spectrum of scientific community is still unable to invent an absolute therapeutic agent for COVID-19. Considering such a fact, drug repurposing strategies seem a truly viable approach to develop novel therapeutic interventions.
    UNASSIGNED: Drug repurposing explores previously approved drugs of known safety and pharmacokinetics profile for possible new effects, reducing the cost, time, and predicting prospective side effects and drug interactions. COVID-19 virulent machinery appeared similar to other viruses, making antiviral agents widely repurposed in pursuit for curative candidates. Our main protease pharmacophoric study revealed multiple features and could be a probable starting point for upcoming research.
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  • 文章类型: Journal Article
    在COVID-19大流行爆发后,寻找治疗方法/药物的研究活动激增。一直有针对传统药物的药物再利用研究。同时,许多研究人员试图在计算机上找到传统药物的证据。与新发现的研究兴趣相称的文章发表量有了很大的增加。这种情况激发了作者对与COVID-19大流行有关的众多出版物的全面了解,并希望获得有希望的药物线索。
    这篇评论文章是对最近刊登的精选论文的评论的混合设计和制作的,目的是为了关注COVID-19的情况,以及作者所做的计算机工作。本综述的结果强调了对有希望的药物线索进行全面MDS分析的建议。将计算机工作作为审查的补充,是由Toelzer及其同事最近发表的一篇文章推动的。游离脂肪酸的计算机模拟研究在该领域是新颖的,它支持了对药物线索的进一步MDS分析,以管理COVID-19大流行。
    所进行的审查揭示了对MDS分析的必要性,以及对药物受体调节位点的药理学性质进行预测的其他计算机模拟方法的应用。此外,目前的分析将有助于制定补充药物的新配方。
    UNASSIGNED: Following the outbreak of the COVID-19 pandemic, there was a surge of research activity to find methods/drugs to treat it. There has been drug-repurposing research focusing on traditional medicines. Concomitantly, many researchers tried to find in silico evidence for traditional medicines. There is a great increase in article publication to commensurate the new-found research interests. This situation inspired the authors to have a comprehensive understanding of the multitude of publications related to the COVID-19 pandemic with a wish to get promising drug leads.
    UNASSIGNED: This review article has been conceived and made as a hybrid of the review of the selected papers advertised recently and produced in the interest of the COVID-19 situation, and in silico work done by the authors. The outcome of the present review underscores a recommendation for thorough MDS analyses of the promising drug leads. The inclusion of in silico work as an addition to the review was motivated by a recently published article of Toelzer and colleagues. The in silico investigation of free fatty acids is novel to the field and it buttresses the further MDS analysis of drug leads for managing the COVID-19 pandemic.
    UNASSIGNED: The review performed threw light on the need for MDS analyses to be considered together with the application of other in silico methods of prediction of pharmacologic properties directing towards the sites of drug-receptor regulation. Also, the present analysis would help formulate new recipes for complementary medicines.
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  • 文章类型: Journal Article
    背景:植物是可变数量的有价值的次级代谢产物的储存库,具有生药学和药理学意义,有可能在未来成为超级药物。这些代谢物的体内生产受到生物和非生物胁迫的影响,导致各种植物化学物质及其衍生物的持续积累,可用于设计和开发未来的潜在药物。本研究的目的是回顾医学上重要的次生代谢产物的存在以及探索不足的杂草植物Hyptissuaveolens(L.)Poit。,探索该植物开发和设计未来药物的潜力。
    属于唇形科的Hyptissuaveolens是重要的药用植物化学物质的丰富来源,如精油,单宁,皂苷,酚类物质,黄酮类化合物,萜类化合物,生物碱,和固醇。这些化合物中的一种或多种具有抗氧化作用,抗炎,抗痉挛,防腐剂,抗癌,抗溃疡,抗菌,抗菌,抗病毒,抗真菌药,抗糖尿病,抗生育,发汗症,反皮肤,anticatarrhal,抗风湿,抗溃疡,胃保护,免疫调节,镇痛药,和抗病毒活性。
    结论:菌泡病含有独特的萜类代谢产物,如菌泡酸,舒韦洛尔,硫酸甲酯,β-谷甾醇,熊果酸,和酚类化合物,如芳香酸,有潜力替代传统药物作为抗耐药和新出现的细菌和病毒病原体的治疗剂的罗莎二酸甲酯。五环三萜类,据报道,熊果酸对导致目前COVID-19大流行的SARS-CoV2和HIV病毒具有有效的抗病毒反应,迄今为止,尚无有效的疫苗。熊果酸具有调节主要蛋白酶(Mpro)活性的能力,这对于病毒复制和颗粒组装所需的SARS-CoV2复制酶-转录酶机制的加工至关重要。
    BACKGROUND: Plants are the repository of variable number of valuable secondary metabolites that bears pharmacognostic and pharmacological implications having potentiality to emerge as super drugs in future. In-vivo production of these metabolites is influenced by the biotic and abiotic stresses resulting in continuous accumulation of diverse phytochemicals and their derivatives that can be useful in designing and developing potential drugs for future. The aim of the present study is to review the existence of medicinally important secondary metabolites and possible pharmacological and pharmacognostic importance of under-explored weed plant species Hyptis suaveolens (L.) Poit., to explore the potentiality of the plant for developing and designing the drugs for future.
    UNASSIGNED: Hyptis suaveolens belonging to family Lamiaceae is the rich source of medicinally important phytochemicals like essential oils, tannins, saponins, phenols, flavonoids, terpenoids, alkaloids, and sterols. One or many of these compounds have antioxidative, anti-inflammatory, antispasmodic, anti-septic, anti-cancer, anti-ulcer, antimicrobial, antibacterial, antiviral, antifungal, anti-diabetic, anti-fertility, diaphoretics, anticutaneous, anticatarrhal, antirheumatic, anti-ulcer, gastroprotective, immunomodulatory, analgesic, and antiviral activity.
    CONCLUSIONS: Hyptis suaveolens contains unique terpenoid metabolites like suaveolic acid, suaveolol, methyl suaveolate, beta-sitosterol, ursolic acid, and phenolic compound like rosamarinic acid, methyl rosamarinate that have potentiality to substitute the traditional drugs as therapeutic agent against the resistant and newly emerged bacterial and viral pathogens. Pentacyclic triterpenoid, ursolic acid have been reported to have effective antiviral response against the SARS-CoV2 responsible for the present COVID-19 pandemic and HIV virus for which no effective vaccines are available till date. Ursolic acid has the ability to modulate the activity of main protease (Mpro) that is essential for processing of SARS-CoV2 replicase-transcriptase machinery needed for viral replication and particle assembly.
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  • 文章类型: Journal Article
    尽管2019年冠状病毒病(COVID-19)具有毒力和高致死率,没有具体的抗病毒治疗存在,直到目前的时刻。正在探索具有免疫促进潜力的天然药物,例如蜂产品,作为可能的治疗方法。蜂蜜和蜂胶含有丰富的生物活性化合物,能表达强烈的抗菌作用,杀菌,抗病毒,抗炎,免疫调节,和抗氧化活性。这篇综述研究了蜜蜂蜂蜜和蜂胶的抗COVID-19作用的文献,目的是优化这些方便的产品作为感染严重急性呼吸道综合症-冠状病毒-2(SARS-CoV-2)的人的预防性或辅助治疗的用途。分子模拟表明蜂胶和蜂蜜中的类黄酮(例如,芦丁,柚皮苷,咖啡酸苯酯,木犀草素,和ArtepillinC)可能会抑制宿主细胞中的病毒刺突融合,引发细胞因子风暴的病毒-宿主相互作用,和病毒复制。类似于强效抗病毒药物Remdesivir,芦丁,蜂胶乙醇提取物,蜂胶脂质体在体外抑制SARS-CoV-2的非结构蛋白,这些化合物与柚皮苷一起抑制了SARS-CoV-2在VeroE6细胞中的感染。纳米载体递送的蜂胶提取物比乙醇提取物对SARS-CoV-2表现出更好的抗病毒作用。在一条线上,住院的COVID-19患者接受绿色巴西蜂胶或蜂蜜和Nigellasativa的组合,表现出更早的病毒清除,症状恢复,出院,死亡率低于仅接受标准治疗的同行。因此,使用蜂产品作为COVID-19的辅助治疗可能产生有益效果。讨论了对治疗结果的影响以及未来研究中应考虑的问题。
    Despite the virulence and high fatality of coronavirus disease 2019 (COVID-19), no specific antiviral treatment exists until the current moment. Natural agents with immune-promoting potentials such as bee products are being explored as possible treatments. Bee honey and propolis are rich in bioactive compounds that express strong antimicrobial, bactericidal, antiviral, anti-inflammatory, immunomodulatory, and antioxidant activities. This review examined the literature for the anti-COVID-19 effects of bee honey and propolis, with the aim of optimizing the use of these handy products as prophylactic or adjuvant treatments for people infected with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Molecular simulations show that flavonoids in propolis and honey (e.g., rutin, naringin, caffeic acid phenyl ester, luteolin, and artepillin C) may inhibit viral spike fusion in host cells, viral-host interactions that trigger the cytokine storm, and viral replication. Similar to the potent antiviral drug remdesivir, rutin, propolis ethanolic extract, and propolis liposomes inhibited non-structural proteins of SARS-CoV-2 in vitro, and these compounds along with naringin inhibited SARS-CoV-2 infection in Vero E6 cells. Propolis extracts delivered by nanocarriers exhibit better antiviral effects against SARS-CoV-2 than ethanolic extracts. In line, hospitalized COVID-19 patients receiving green Brazilian propolis or a combination of honey and Nigella sativa exhibited earlier viral clearance, symptom recovery, discharge from the hospital as well as less mortality than counterparts receiving standard care alone. Thus, the use of bee products as an adjuvant treatment for COVID-19 may produce beneficial effects. Implications for treatment outcomes and issues to be considered in future studies are discussed.
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  • 文章类型: Journal Article
    2019年冠状病毒病(COVID-19)大流行继续挑战世界各地的医疗保健系统。科学家和制药公司迅速做出反应,以指数速度将潜在的治疗方法推进临床试验。使用remdesivir和地塞米松已经实现了最初令人鼓舞的结果。然而,研究仍在继续,以确定更好的临床相关疗法,这些疗法既可以作为预防感染的预防措施,也可以作为限制COVID-19严重程度并大大降低死亡率的治疗方法。以前,我们回顾了临床试验中阻断病毒生命周期早期阶段的潜在治疗方法.在这次审查中,我们总结了阻断/抑制病毒生命周期进入后阶段的潜在抗COVID-19治疗药物.这篇综述不仅介绍了临床研究中潜在疗法的化学结构和机制,即,在临床试验中列出。gov,但它也描述了临床试验的相关结果。还描述了它们的抗炎/免疫调节作用。综述的疗法包括小分子,多肽,和单克隆抗体。在分子水平上,治疗剂靶向促进病毒感染的进入后阶段的病毒蛋白质或过程。常见的靶标是病毒RNA依赖性RNA聚合酶(RdRp)和病毒蛋白酶如木瓜蛋白酶样蛋白酶(PLpro)和主蛋白酶(Mpro)。总的来说,我们的目标是提供抗COVID-19疗法的最新细节,以促进其在抗击大流行中的潜在有效用途。
    The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.
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