Frontiers in drug discovery最新文献_第9页

Nanobodies: COVID-19 and Future Perspectives 纳米体:COVID-19和未来展望

Frontiers in drug discovery Pub Date : 2022-07-18 DOI: 10.3389/fddsv.2022.927164

Guillermo Valenzuela-Nieto, Zaray Miranda-Chacón, Constanza Salinas-Rebolledo, Ronald Jara, Alexei Cuevas, Anne D. Berking, A. Rojas-Fernandez

引用次数: 7

Reszinate—A Phase 1/2 Randomized Clinical Trial of Zinc and Resveratrol Utilizing Home Patient-Obtained Nasal and Saliva Viral Sampling Reszinate-A:锌和白藜芦醇的1/2期随机临床试验，利用家庭患者获得的鼻腔和唾液病毒取样

Frontiers in drug discovery Pub Date : 2022-07-15 DOI: 10.3389/fddsv.2022.910124

H. Kaplan, Kai Wang, Kimberly M. Reeves, J. Scanlan, Christopher C. Nunn, D. Kieper, Joshua L. Mark, Inyoul Y. Lee, Rachel Liu, R. Jin, Michael J. Bolton, J. Goldman

{"title":"Reszinate—A Phase 1/2 Randomized Clinical Trial of Zinc and Resveratrol Utilizing Home Patient-Obtained Nasal and Saliva Viral Sampling","authors":"H. Kaplan, Kai Wang, Kimberly M. Reeves, J. Scanlan, Christopher C. Nunn, D. Kieper, Joshua L. Mark, Inyoul Y. Lee, Rachel Liu, R. Jin, Michael J. Bolton, J. Goldman","doi":"10.3389/fddsv.2022.910124","DOIUrl":"https://doi.org/10.3389/fddsv.2022.910124","url":null,"abstract":"Background: Safe, effective, and inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity, and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations.Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 g daily for 5 days versus placebos in outpatients with SARS-CoV-2 was carried out from 9/21/2020–1/22/2021 in Seattle, Washington. Viral shedding was followed with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene days 1–7, 10, and 14. Patients filled out a web-based questionnaire on days 1–14 to report symptoms, vital signs and adherence to the study intervention. The study was posted as Clinical Trials.gov NCT04542993 on 9 September 2020.Results: A total of 30 participants (14 treatment; 16 placebos) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups, nor in the resolution of symptoms. There was a trend toward a more rapid decrease in symptoms in the treatment group, though this was not statistically significant in the GLM model. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with a good correlation.Conclusion: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment. Viral shedding correlates well between patient-obtained home nasal swabs and saliva sampling.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42536398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Overcoming Market Failures in Pandemic Drug Discovery Through Open Science: A Canadian Solution 通过开放科学克服流行病药物发现的市场失灵:加拿大的解决方案

Frontiers in drug discovery Pub Date : 2022-05-26 DOI: 10.3389/fddsv.2022.898654

E. Gold, A. Edwards

{"title":"Overcoming Market Failures in Pandemic Drug Discovery Through Open Science: A Canadian Solution","authors":"E. Gold, A. Edwards","doi":"10.3389/fddsv.2022.898654","DOIUrl":"https://doi.org/10.3389/fddsv.2022.898654","url":null,"abstract":"Among the lessons learned from the COVID-19 pandemic is the need to develop antiviral drugs poised to treat the next pandemic. Unfortunately, traditional drug development economic models, centered principally on patents, are ineffective to induce private sector investment due to unpredictable timing and cause of the next pandemic. As a result, illustrated by the COVID-19 pandemic, it is the public and philanthropic sectors sectors that overwhelmingly fund the development of innovative vaccines and therapies. To meet the need for proactive antiviral medicines in advance of the next pandemic, new models of drug development are needed. Open science partnerships (OSPs) show promise in this regard. Rather than rely principally on patents and private investment, OSPs combine a variety of academic, philanthropic, governmental, and private sector incentives to share knowledge and develop and test antiviral drugs. Private sector investments are, within an OSP, not only leveraged against investments by other actors, but predicated on gaining regulatory data exclusivity, a known and secure form of commercial advantage. Building on domestic expertise in OSPs, Canadian leaders created the Viral Interruption Medicines Initiative, a not-for-profit OSP, to develop pandemic ready-antivirals and address other areas of market failure.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45960554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Furin and COVID-19: Structure, Function and Chemoinformatic Analysis of Representative Active Site Inhibitors Furin与新冠肺炎：代表性活性位点抑制剂的结构、功能和化学信息学分析

Frontiers in drug discovery Pub Date : 2022-05-10 DOI: 10.3389/fddsv.2022.899239

B. Villoutreix, I. Badiola, A. Khatib

引用次数: 5

Peptide-Based Strategies Against SARS-CoV-2 Attack: An Updated In Silico Perspective 基于肽的抗SARS-CoV-2攻击策略:最新的计算机视角

Frontiers in drug discovery Pub Date : 2022-05-10 DOI: 10.3389/fddsv.2022.899477

G. Moroy, P. Tufféry

{"title":"Peptide-Based Strategies Against SARS-CoV-2 Attack: An Updated In Silico Perspective","authors":"G. Moroy, P. Tufféry","doi":"10.3389/fddsv.2022.899477","DOIUrl":"https://doi.org/10.3389/fddsv.2022.899477","url":null,"abstract":"Because of its scale and suddenness, the SARS-CoV-2 pandemic has created an unprecedented challenge in terms of drug development. Apart from being natural candidates for vaccine design, peptides are a class of compounds well suited to target protein-protein interactions, and peptide drug development benefits from the progress of in silico protocols that have emerged within the last decade. Here, we review the different strategies that have been considered for the development of peptide drugs against SARS-CoV-2. Thanks to progress in experimental structure determination, structural information has rapidly become available for most of the proteins encoded by the virus, easing in silico analyses to develop drugs or vaccines. The repurposing of antiviral/antibacterial peptide drugs has not been successful so far. The most promising results, but not the only ones, have been obtained targeting the interaction between SARS-CoV-2 spike protein and the Angiotensin-Converting Enzyme 2, which triggers cellular infection by the virus and its replication. Within months, structure-based peptide design has identified competing for picomolar candidates for the interaction, proving that the development of peptide drugs targeting protein-protein interactions is maturing. Although no drug specifically designed against SARS-CoV-2 has yet reached the market, lessons from peptide drug development against SARS-CoV-2 suggest that peptide development is now a plausible alternative to small compounds.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44522036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Advances in Modelling COVID-19 in Animals COVID-19动物模型研究进展

Frontiers in drug discovery Pub Date : 2022-05-02 DOI: 10.3389/fddsv.2022.899587

Petr Nickl, Miles Joseph Raishbrook, L. Syding, R. Sedláček

{"title":"Advances in Modelling COVID-19 in Animals","authors":"Petr Nickl, Miles Joseph Raishbrook, L. Syding, R. Sedláček","doi":"10.3389/fddsv.2022.899587","DOIUrl":"https://doi.org/10.3389/fddsv.2022.899587","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense-single stranded RNA virus and the cause of the coronavirus disease 2019 (COVID-19). The World Health Organisation has confirmed over 250 million cases with over 5.1 million deaths as a result of this pandemic since December 2019. A global outbreak of such intensity and perseverance is due to the novelty of SARS-CoV2 virus, meaning humans lack any pre-existing immunity to the virus. Humanised animal models, from rodents to primates, simulating SARS-CoV2 transmission, cell entry and immune defence in humans have already been crucial to boost understanding of its molecular mechanisms of infection, reveal at-risk populations, and study the pathophysiology in vivo. Focus is now turning towards using this knowledge to create effective vaccines and therapeutic agents, as well as optimise their safety for translatable use in humans. SARS-CoV2 possesses remarkable adaptability and rapid mutagenic capabilities thus exploiting innovative animal models will be pivotal to outmanoeuvre it during this pandemic. In this review, we summarise all generated SARS-CoV2-related animal models to date, evaluate their suitability for COVID-19 research, and address the current and future state of the importance of animal models in this field.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41928730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Developing Small-Molecule Inhibitors of Protein-Protein Interactions Involved in Viral Entry as Potential Antivirals for COVID-19 开发参与病毒进入的蛋白质相互作用的小分子抑制剂作为潜在的COVID-19抗病毒药物

Frontiers in drug discovery Pub Date : 2022-04-25 DOI: 10.3389/fddsv.2022.898035

P. Buchwald

{"title":"Developing Small-Molecule Inhibitors of Protein-Protein Interactions Involved in Viral Entry as Potential Antivirals for COVID-19","authors":"P. Buchwald","doi":"10.3389/fddsv.2022.898035","DOIUrl":"https://doi.org/10.3389/fddsv.2022.898035","url":null,"abstract":"Blocking protein-protein interactions (PPIs) involved in the initiation of the cell attachment and entry of viruses is an important antiviral mechanism of action including for neutralizing antibodies. Doing it with small-molecule inhibitors (SMIs) is challenging, as it is for all other PPIs, and might require the exploration of chemical space beyond that of typical drug-like structures. However, it could lead to new antiviral agents suitable for oral administration and acting on alternative targets, considerations that are essential for the development of widely acceptable and broad-spectrum preventive or curative therapeutics. Fostemsavir, an antiretroviral that acts via blocking of the gp120–CD4 PPI, supports the feasibility of the concept. Here, a brief review of relevant drug design considerations is presented together with a summary of the progress made toward the identification of SMIs targeting the PPI between the SARS-CoV-2 spike protein and ACE2 that initiates the viral attachment and cellular entry of this coronavirus causing the COVID-19 pandemic. SMIs identified in various screening assays that were also confirmed to have antiviral activity in a live virus or pseudovirus assay with an IC50 < 30 µM so far include several organic dyes (methylene blue, Evans blue, Congo red, direct violet 1), verteporfin, DRI-C23041, and cannabigerolic and cannabidiolic acids. While specificity and activity profiles still need improvement, results so far already provide proof-of-principle evidence for the feasibility of SMIs targeting the SARS-CoV-2-S–hACE2 PPI. Methylene blue, which is approved for clinical use, is orally bioactive, and could act by multiple mechanisms of action, might have potential for repurposing for COVID-19 prevention and treatment.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46304005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

COVID-19 Therapies: Protease Inhibitions and Novel Degrader Strategies 新冠肺炎治疗：蛋白酶抑制剂和新型降解剂策略

Frontiers in drug discovery Pub Date : 2022-04-13 DOI: 10.3389/fddsv.2022.892057

M. Reboud-Ravaux, C. El Amri

引用次数: 2

Addressing Antibiotic Failure—Beyond Genetically Encoded Antimicrobial Resistance 解决抗生素失效——超越基因编码的抗生素耐药性

Frontiers in drug discovery Pub Date : 2022-04-08 DOI: 10.3389/fddsv.2022.892975

Evan F. Haney, R. Hancock

引用次数: 7

The Need for Speed and Efficiency: A Brief Review of Small Molecule Antivirals for COVID-19 对速度和效率的需求:COVID-19小分子抗病毒药物综述

Frontiers in drug discovery Pub Date : 2022-03-30 DOI: 10.3389/fddsv.2022.837587

A. C. Puhl, T. Lane, Fabio Urbina, S. Ekins

{"title":"The Need for Speed and Efficiency: A Brief Review of Small Molecule Antivirals for COVID-19","authors":"A. C. Puhl, T. Lane, Fabio Urbina, S. Ekins","doi":"10.3389/fddsv.2022.837587","DOIUrl":"https://doi.org/10.3389/fddsv.2022.837587","url":null,"abstract":"While we currently have multiple highly effective vaccines approved for use against SARS-CoV-2 in the USA and other countries, there are far fewer small molecule antivirals approved to date. The emergence of the latest SARS-CoV-2 variant, Omicron which is heavily mutated in the spike protein, is also raising concerns about the effectiveness of these current vaccines and increasing the call for more therapeutic options. At the time of writing only remdesivir is approved by the FDA while molnupiravir (already approved in the United Kingdom) and Paxlovid (PF-07321332) have emergency use authorizations from the FDA. Repurposed molecules, such as dexamethasone and baricitinib, have been authorized for emergency use in some countries and are used in combination with remdesivir. After 2 years we are only now starting to see the progression of further molecules through animal models to assess their efficacy before clinical trials. As datasets accumulate from both in vitro and in vivo animal efficacy models, this may allow us to understand the physicochemical properties necessary for antiviral activity and enable the search for additional antivirals. We now summarize 25 small molecule drugs that are either approved, in the process of approval or in the pipeline for COVID which have both in vitro and in vivo data. We demonstrate that these drugs are structurally diverse and cover a wide chemistry space. This information may aid our understanding of what it takes to be a promising treatment for COVID-19 and propose how to discover antivirals faster and more efficiently for the next pandemic. Graphical Abstract","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45068868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8