Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.

To Speed up the Development and Industrialization of Natural Drugs in China

1.The Current Situation Facing China's accession to the WTO,our pharmaceutical industries must prepare to meet extremely strong competition,because 97% of the synthetic medicines and antibiotics marketed in the country are copies of foreign products.

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The higher plant-derived sesquiterpene,quinoline alkaloids,and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed.Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed.The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P.falciparum.To identify these novel scaffolds,we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data.Natural products were assigned to different structural classes using NPClassifier.To identify the most promising chemical scaffolds,we then correlated natural compound class with bioactivity and other data,namely(i)potency,(ii)resistance index,(iii)selectivity index and(iv)physicochemical properties.We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data.From this analysis we identified the top-ranked natural product pathway as the alkaloids.The top three ranked super classes identified were(i)pseudoalkaloids,(ii)naphthalenes and(iii)tyrosine alkaloids and the top five ranked classes(i)quassinoids(of super class triterpenoids),(ii)steroidal alkaloids(of super class pseudoalkaloids)(iii)cycloeudesmane sesquiterpenoids(of super class triterpenoids)(iv)isoquinoline alkaloids(of super class tyrosine alkaloids)and(v)naphthoquinones(of super class naphthalenes).Launched chemical space of these identified classes of compounds was,by and large,distinct from that of‘legacy’antimalarial drugs.Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs.These molecules have the potential to be developed into new antimalarial drugs.

Marine natural products with anti-inflammation effects

The ocean possesses a complex setting with high pressure,high salinity,oligotrophy,low temperature and weak illumination conditions.To survive and evolve in such harsh surroundings,marine organisms metabolize a series of chemicals known as secondary metabolites which indicate structural and functional diversity to adapt interspecific survival competition.During recent decades,the anti-inflammatory property of marine natural products has come under scrutiny as inflammation involves in the vast majority of diseases.Correspondingly,a myriad of marine bioactive molecules including terpenes,polypeptides,polysaccharides,sterols and many others may bring a new insight into inflammation therapies with multifarious sources and minimal side effects.And a better understanding of their mechanisms of anti-inflammation may lead to better treatments for numerous diseases.Herein,the research progress of marine-derived anti-inflammation compounds and the relevant mechanisms were reviewed,to provide a basis for the research and development of anti-inflammatory marine drugs.

中药源手性药物研究进展与述评

手性化合物在自然界中广泛存在。许多天然药物分子均含有手性中心,且药物的药理活性与分子的手性结构密切相关。在已知的传统中药体系中,存在着大量的手性药物分子,这些药物分子被广泛应用于各类临床治疗诊断中。因此,研究手性分子在中药中的存在形式和作用机制,对于深入探索中药的药理、药效至关重要。以中药中的手性天然药物分子为研究对象,旨在阐述其手性结构、化学与生物合成方法、药理活性与手性的相关性,以及手性药物在临床应用中的重要进展,探讨中药源手性药物研发的前景。

基于人工智能的药物研发:目前的进展和未来的挑战

近年来,人工智能在药物研发领域得到了广泛的应用。特别是自然语言处理技术在预训练模型的出现后有了非常显著的提高,在此基础上,图神经网络的引入也使得药物研发变得更加准确和高效。为了使药物研发者更加系统全面地了解人工智能在药物研发中的应用,本文介绍了人工智能中的前沿算法,同时阐述了人工智能在药物小分子设计、虚拟筛选、药物再利用以及药物性质预测等多方面的应用场景,最后探讨它在未来药物研发中的机遇与挑战。

Research and development of Chinese anti-COVID-19 drugs

The outbreak and spread of coronavirus disease 2019(COVID-19)highlighted the importance and urgency of the research and development of therapeutic drugs.Very early into the COVID-19 pandemic,China has begun developing drugs,with some notable progress.Herein,we summarizes the anti-COVID-19 drugs and promising drug candidates originally developed and researched in China.Furthermore,we discussed the developmental prospects,mechanisms of action,and advantages and disadvantages of the anti-COVID-19 drugs in development,with the aim to contribute to the rational use of drugs in COVID-19 treatment and more effective development of new drugs against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and the variants.Neutralizing antibody is an effective approach to overcome COVID-19.However,drug resistance induced by rapid virus mutation will likely to challenge neutralizing antibodies.Taking into account current epidemic trends,small molecule drugs have a crucial role in fighting COVID-19 due to their significant advantage of convenient administration and affordable and broad-spectrum.Traditional Chinese medicines,including natural products and traditional Chinese medicine prescriptions,contribute to the treatment of COVID-19 due to their unique mechanism of action.Currently,the research and development of Chinese anti-COVID-19 drugs have led to some promising achievements,thus prompting us to expect even more rapidly available solutions.

仙人掌的天然活性成分研究回顾

该综述参阅了近 2 0年来国内外有关仙人掌的研究报导和有关书刊 ,对各类仙人掌中的天然活性成分 ,如生物碱类尤其是墨斯卡林、黄酮类如黄酮醇、甾醇类如谷甾醇以及其他成分如油脂、蛋白质、多糖类、微量元素等的研究状况进行了全面地综合和归类 ,对仙人掌的开发应用情况及前景做了细致的分析和展望。

天然药物的研究与开发

天然药物是医药的重要组成部分 ,是我国新药研究和开发的重点 .本文论述了天然药物研究的重要性、研究的重点和天然药物开发的程序 .

天然药物防治非酒精性和酒精性脂肪肝的研究进展

本文综述了近年来天然药物、有效部位及单体活性成分用于治疗非酒精性脂肪肝和酒精性脂肪肝的研究进展。文中列举了122种天然药物的治疗效果,并将其分为生物碱类、总黄酮和总酚酸类、单体酚酸、萜类和甾醇类、总苷与总酯类、氨基酸和杂环类、多糖与聚糖类、肽和不饱和脂肪酸类、香豆素和色素类、单味植物药制剂、动物药与真菌药共11大类。文中还对未来非酒精性脂肪肝和酒精性脂肪肝的新药研发方向进行了评述。

细胞色素P450酶诱导/抑制的研究方法及在药物研究中的应用

细胞色素P450(CYP450)在外源及内源物质的生物转化过程中发挥着至关重要的作用,是肝脏中重要的药物代谢酶。CYP450酶活性/含量的改变直接影响了经其代谢的药物在体内的有效量和作用时间,与药效和用药安全性有密切的联系。因此,了解药物对CYP450酶可能存在的诱导或抑制作用是药物研究过程中不可缺少的研究内容。本文综述了近年来研究CYP450酶诱导/抑制水平和机制的试验方法以及在药物、尤其是在天然产物研究中的应用。

紫杉醇:具有里程碑意义的天然抗癌药物

紫杉醇是从红豆杉树皮中分离得到的微量单体成分,作为世界上最优秀的植物抗癌药,紫杉醇及其衍生物是临床上常用的广谱抗癌药。自20世纪70年代发现紫杉醇后,科学家对此类化合物的构效关系、结构修饰、药理药效方面开展了大量研究,并开发出泰素、多西他赛、卡巴他赛、拉洛他赛、信立他赛、康莫他赛等抗癌药。直到40年后的今天,科学家对紫杉醇的研究依然活跃,对其生物合成、真菌培养、新剂型开发等方面也成为新的研究方向。作为源于天然的单体成分开发成新药的成功典范,紫杉醇类化合物的研发历程对当前开发天然新药提供有益的借鉴。本文对紫杉醇的研发及最新进展进行综述,回顾其开发历程及相关研究,以期为天然药物的开发带来新的思考。

抗病原真菌药物的研究进展

本文概述了抗病原真菌药物的作用机制、研究现状和发展趋势。同时,结合本课题组的研究结果,对从甾体皂苷中寻找新型抗菌药物提出展望。

以全球案例教学法提升天然药物研发课程的应用性和国际化视野

在药学学位改革和"双一流"等国家政策的指导下,应用性和国际化已成为药学教育的重要发展方向。以浙江大学药学院天然药物研发课程为例,分析了之前课程中存在的问题,以贯彻国家教育政策、提高课程的生动性、实用性和国际化视野为目标,进行了有益的探索和完善,以期为国内高校建设相关类似课程提供参考。

高职高专药学专业《天然药物鉴定技术》基于工作过程的教学改革

以"基于工作过程"的职业教育理念,从课程目标确立、教学内容优化、职业能力培养以及教学方法改进等方面,针对高职高专药学专业《天然药物鉴定技术》课程进行了课程开发与教学改革的实践研究,认为教学各环节均应以培养学生职业能力为主线,以培养一线高素质、高技能、应用型专门人才为目标,从而体现高职高专职业教育的特色。

天然小分子、表象药理与药物作用的机制

本文主要从天然(中药)小分子与化学合成小分子的理念异同、表象药理与特异性靶点及其作用机制的异同等方面对该类小分子成分的特点及其相关的药理学研究的一些概念进行了探讨。由于天然(中药)小分子来源的非目的性,具有体内作用靶点多样性和作用机制广泛性的特点。因此,在药理研究中,要进行相关作用靶点背景的筛选,以确定作用靶点和作用机制的相关性。最后进行作用靶点和作用机制特异性的确证。为了更好的理解和掌握小分子作用的相关性和特异性,进而促进天然(中药)小分子新药的研究,本文对此进行了较为系统深入的探讨。

国内外应用天然药物的有效部位、单体防治肝纤维化的研究进展

目的:综述近年来用于治疗肝纤维化天然药物的有效部位及单体活性成分的研究进展。方法:对34种天然药物的生物碱类、总黄酮和总酚酸类、单体酚酸类、萜类及其苷和甾醇类、木脂素类、氨基酸/多肽和杂环类、多糖类、香豆素类进行分析。结果:已报道的34种天然药物对肝纤维化均具有一定的治疗效果。结论:对未来治疗肝纤维化的新药研发方向进行展望。

楚雄发展天然药业的思考

本文分析了楚雄州天然药物业的基础和比较优势,提出了楚雄州天然药物业的发展思路、对策。

再论药品专利与新药研究开发(一)

本文从不同的侧面论述了当代新药研究开发面临的新挑战和机遇,新药研究开发所具有的主要特征和规律,以及重要的发展趋势和战略。

基于内质网应激的抗肿瘤药物研发

在缺氧、钙代谢紊乱、氧化应激等条件下,细胞内质网功能受到干扰,未折叠或错误折叠蛋白积聚,将产生内质网应激(endoplasmic reticulum stress,ERS)效应。早期ERS可促使肿瘤细胞存活,但长时间或严重的ERS可诱导肿瘤细胞产生凋亡等效应,这使得基于ERS的抗肿瘤药物研发成为可能。该文主要介绍当前基于ERS的抗肿瘤药物研发概况,总结具有诱导ERS效应的天然产物,并在此基础上对基于ERS的抗肿瘤药物研发进行分析,以期为相关领域的发展提供参考。