Drug repurposing against SARS-CoV-2 using computational approaches

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a critical need for treatments to reduce morbidity and mortality associated with this disease. However, traditional drug development takes many years, which is not practical solution given the current pandemic. Therefore, a viable option is to repurpose existing drugs. The structural data of several proteins vital for the virus became available shortly after the start of the pandemic. In this review, we discuss the importance of these targets and their available potential inhibitors predicted by the computational approaches. Among the hits identified by computational approaches, 35 candidates were suggested for further evaluation, among which ten drugs are in clinical trials (Phase III and IV) for treating Coronavirus 2019 (COVID-19).     

Therapeutic targets and early stage clinical trials for pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive, and irreversible fatal interstitial lung disease. Although many drugs have failed in clinical trials, these failures improved the understanding of the pathogenesis of IPF. Currently, there are two drugs approved for IPF that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to further reduce or even halt the progression of the disease.

Areas covered: We highlight the recent information on the therapeutic targets currently explored in early stage clinical trials and discuss the potential for new therapy and the limitation of basic research in the treatment of IPF.

Expert opinion: A key challenge in the coming years will lie in deciding which compounds to combine and how to evaluate combination therapies in clinical trials. The drugs most likely to provide additive efficacy when used in combination with one of the approved therapies are those with alternative, complementary, or synergistic mechanisms of action.     

Combining computational and experimental evidence on the activity of antimalarial drugs on papain-like protease of SARS-CoV-2: A repurposing study

The development of inhibitors that target the papain-like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causing coronavirus disease 2019 (COVID-19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS-CoV-2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a μM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.     

Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein

ContextCoronavirus disease 2019 is a global pandemic. Studies suggest that folic acid has antiviral effects. Molecular docking shown that folic acid can act on SARS-CoV-2 Nucleocapsid Phosphoprotein (SARS-CoV-2 N).ObjectiveTo identify novel molecular therapeutic targets for SARS-CoV-2.Materials and methodsTraditional Chinese medicine targets and virus-related genes were identified with network pharmacology and big data analysis. Folic acid was singled out by molecular docking, and its potential target SARS-CoV-2 N was identified. Inhibition of SARS-CoV-2 N of folic acid was verified at the cellular level.ResultsIn total, 8355 drug targets were potentially involved in the inhibition of SARS-CoV-2. 113 hub genes were screened by further association analysis between targets and virus-related genes. The hub genes related compounds were analysed and folic acid was screened as a potential new drug. Moreover, molecular docking showed folic acid could target on SARS-CoV-2 N which inhibits host RNA interference (RNAi). Therefore, this study was based on RNAi to verify whether folic acid antagonises SARS-CoV-2 N. Cell-based experiments shown that RNAi decreased mCherry expression by 81.7% (p < 0.001). This effect was decreased by 8.0% in the presence of SARS-CoV-2 N, indicating that SARS-CoV-2 N inhibits RNAi. With increasing of folic acid concentration, mCherry expression decreased, indicating that folic acid antagonises the regulatory effect of SARS-CoV-2 N on host RNAi.Discussion and conclusionsFolic acid may be an antagonist of SARS-CoV-2 N, but its effect on viruses unclear. In future, the mechanisms of action of folic acid against SARS-CoV-2 N should be studied.     

重大疫情下口腔科临床试验管理策略和防控建议

新型冠状病毒肺炎疫情波及全球,受疫情影响大量的临床试验工作处于暂停、延缓状态,各地临床试验机构纷纷启动一系列应急管理措施。口腔科临床试验中各种检查需医患近距离接触,操作时易产生飞沫和气溶胶,有较高的交叉感染风险。此次疫情对口腔专业临床试验的运行带来巨大挑战。本文根据疫情防控要求和重大突发公共卫生事件下的临床试验管理共识,结合本机构相关工作指引和临床试验相关法规,对疫情下口腔科临床试验运行管理及临床试验过程中防护措施提出建议。旨在为疫情防控期间口腔科临床试验管理人员、研究者及受试者提供帮助。     

Investigational drug therapies in phase I and phase II clinical trials for alcohol use disorders

Introduction: Alcohol use disorder (AUD) is a complex psychiatric condition characterized by craving, compulsive seeking, loss of control of alcohol consumption as well as the emergence of negative emotional states during withdrawal. Despite the large socioeconomic burden of AUD, therapeutic treatment options lag behind.

Areas covered: This review covers pharmacotherapies currently in phase I/II clinical trials for the treatment of AUDs listed on clinicaltrials.gov. We discuss drug therapies that modulate monoamine, GABA/Glutamate, neuropeptide and neuroimmune systems. We examine in depth preclinical and clinical evidence of a select range of these compounds and consider their utility in treating AUDs.

Expert opinion: Current therapeutic options to treat AUD are inadequate at a population level. Currently there are 30 different compounds and one compound combination in phase I/II clinical trials for AUD. These compounds target various aspects of neurotransmitter signaling, neuroimmune modulation, and alcohol metabolism. Almost 75% of these compounds under trial are Food and Drug Administration (FDA) approved for other indications, which may save time and costs in treatment development. Further, development of therapeutics focused on genetic biomarkers and behavioral screening may improve how treatment decisions are made in the future on a case-by-case basis.     

全球新型冠状病毒疫苗及治疗药物研发现状与趋势

截至2021年5月,我国已附条件上市及获批紧急使用了6款新型冠状病毒疫苗(以下简称新冠疫苗)产品,其中包括4款新冠灭活疫苗产品、1款新冠腺病毒疫苗产品以及1款新冠重组疫苗产品.6款疫苗产品均在全球范围内进行了不同阶段的临床试验,临床研究结果在一定程度上证明了疫苗的安全性及预防新型冠状病毒肺炎(COVID-19)疫情的有...     

DNA-based therapeutics and DNA delivery systems: A comprehensive review

The past several years have witnessed the evolution of gene medicine from an experimental technology into a viable strategy for developing therapeutics for a wide range of human disorders. Numerous prototype DNA-based biopharmaceuticals can now control disease progression by induction and/or inhibition of genes. These potent therapeutics include plasmids containing transgenes, oligonucleotides, aptamers, ribozymes, DNAzymes, and small interfering RNAs. Although only 2 DNA-based pharmaceuticals (an antisense oligonucleotide formulation, Vitravene, (USA, 1998), and an adenoviral gene therapy treatment, Gendicine (China, 2003), have received approval from regulatory agencies; numerous candidates are in advanced stages of human clinical trials. Selection of drugs on the basis of DNA sequence and structure has a reduced potential for toxicity, should result in fewer side effects, and therefore should eventually yield safer drugs than those currently available. These predictions are based on the high selectivity and specificity of such molecules for recognition of their molecular targets. However, poor cellular uptake and rapid in vivo degradation of DNA-based therapeutics necessitate the use of delivery systems to facilitate cellular internalization and preserve their activity. This review discusses the basis of structural design, mode of action, and applications of DNA-based therapeutics. The mechanisms of cellular uptake and intracellular trafficking of DNA-based therapeutics are examined, and the constraints these transport processes impose on the choice of delivery systems are summarized. Finally, the development of some of the most promising currently available DNA delivery platforms is discussed, and the merits and drawbacks of each approach are evaluated.     

A micro-sized vaccine based on recombinant Lactiplantibacillus plantarum fights against SARS-CoV-2 infection via intranasal immunization

COVID-19 has globally spread to burden the medical system. Even with a massive vaccination, a mucosal vaccine offering more comprehensive and convenient protection is imminent. Here, a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum (rLP) displaying spike or receptor-binding domain (RBD) was characterized as microparticles, and its safety and protective effects against SARS-CoV-2 were evaluated. We found a 66.7% mortality reduction and 100% protection with rLP against SARS-CoV-2 in a mouse model. The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung. Especially, rLP:RBD significantly decreased pulmonary viral loads. For the first time, our study provides a L. plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.     

抗病毒药物治疗COVID-19的研究进展:临床试验的系统综述

目的： 探讨抗病毒药物治疗新型冠状病毒肺炎（coronavirus disease 2019,COVID-19）的有效性和安全性。方法： 计算机检索PubMed、Embase、medRxiv、中国知网、中国临床试验注册中心、Clinical trials.gov等数据库截止至2020年4月29日有关新型冠状病毒肺炎抗病毒治疗的临床试验,对试验结果进行系统综述。结果： 共纳入20项研究,随机对照研究8项,非随机对照研究3项,回顾性队列研究3项,回顾性病例系列研究4项,观察性研究2项,合计2 299例患者。评价的药物包括瑞德西韦、洛匹那韦/利托那韦、羟氯喹、法匹拉韦、阿比多尔、达诺瑞韦、疏风解毒胶囊和连花清瘟胶囊（颗粒）。所评价的抗病毒药物均未在临床试验中展现出对COVID-19的优越疗效。中成药疏风解毒胶囊和连花清瘟胶囊（颗粒）能明显改善轻型和普通型患者临床症状,提高治疗效果。安全性方面,需要特别关注洛匹那韦/利托那韦的胃肠道不良反应和瑞德西韦的严重不良反应。结论： 目前暂无特效药,重型患者早期可试用瑞德西韦或采用2种以上抗病毒药物联合治疗,轻型和普通型患者可加用中成药辅助治疗。需要更高质量,大样本随机对照试验进一步验证瑞德西韦、羟氯喹、法匹拉韦等药物的疗效。     

Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update

ABSTRACT

Introduction: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent.

Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing 20 potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development.

Expert opinion: So far, 20 compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long noncoding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents.     

COVID-19疫情下某三甲医院1066例发热门诊患者临床资料分析

目的:了解COVID-19疫情下发热门诊患者的临床特征、诊疗流程,为COVID-19防治工作提供数据参考.方法:通过医院电子病历系统、HIS系统、PACS系统,提取某三甲医院2020年1月27日至3月9日所有发热门诊患者的病历资料并进行分析.结果:共纳入患者1066例,以21～30岁居多(31.33％);首发症状排名前...     

Diabetes,inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2

Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and ‘cytokine storm,’ causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.     

The PREDICT (increasing the participation of the elderly in clinical trials) study: the charter and beyond

There is general agreement that the growth of the numbers of older people throughout the world has significant implications for both health and social care and for the prevention and treatment of disease and disability. The optimum use of pharmaceuticals and possibly nutraceuticals is, and will to a greater extent, therefore be of crucial importance. A snapshot of the current status of older people in relation to the issues discussed in this review is provided in an informative report published by Age UK.     

Triple-negative breast cancer brain metastasis: An update on druggable targets,current clinical trials,and future treatment options

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药师参与肿瘤患者新药临床试验伦理审查典型案例分析

目的:探讨肿瘤患者新药临床试验中各种伦理问题的具体表现形式,为提高医疗机构伦理审查的质量和水平提供参考.方法:通过分析14例肿瘤患者新药临床试验典型案例,找出存在的伦理问题.结果:研究方案存在研究基础不充分、纳入排除标准不严谨、对照组设置不合理、揭盲时间不合理等问题;知情同意书存在告知信息不充分、语言表述不准确、补偿与...     

Foundation year 1 doctors and clinical pharmacology and therapeutics teaching. A retrospective view in light of experience

AIMS: To determine whether, in retrospect, first year foundation (FY1) programme doctors believe that their undergraduate education in Clinical Pharmacology and Therapeutics (CPT) has prepared them to prescribe safely and rationally. METHODS: This was a prospective questionnaire survey. Ninety FY1 doctors, employed in the Aberdeen Teaching Hospitals, participated. RESULTS: Seventy-one percent of FY1 doctors completed the survey. Thirty percent of respondents rated their knowledge of CPT as poor or worse and only 8% as good; 74% reported having witnessed an adverse drug reaction (ADR) and 55% a drug-drug interaction, a number of which had resulted in patient morbidity or mortality. Many of these events were reported to have been avoidable or predictable with more extensive undergraduate and postgraduate training. Forty-two percent of respondents stated that they had not been taught enough about avoiding ADRs and 60% about avoiding drug-drug interactions during their undergraduate years. Over 75% of respondents reported high levels of confidence for the unsupervised use of warfarin, nonsteroidal analgesics and opiate analgesics. In retrospect, FY1 doctors would like more undergraduate teaching in prescribing for special patient groups, ADRs, drug interactions, together with CPT in their postgraduate teaching programme. CONCLUSIONS: FY1 doctors believe that their undergraduate and postgraduate training in CPT is insufficient to prescribe safely and rationally. This study adds further weight to the call for an increase in the training of junior doctors in the rational and safe use of medicines.