Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses
针对季节性和高致病性流感病毒的广谱抑制剂的开发
基本信息
- 批准号:10080034
- 负责人:
- 金额:$ 97.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-08 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAddressAdultAnabolismAnimal ModelAnimalsAntiviral AgentsAntiviral TherapyAvian Influenza A VirusBackBioavailableBiological AssayBiological AvailabilityBirdsCanis familiarisCaviaCellsCessation of lifeChemicalsClinicClinicalComplexCytidineDevelopmentDiseaseDisease ManagementDrug ExposureDrug KineticsDrug ScreeningElderlyEligibility DeterminationEstersFailureFamily suidaeFerretsFormulationFrequenciesGenerationsHumanIndustryInfectionInfluenzaInfluenza A Virus, H5N1 SubtypeInfluenza A Virus, H7N9 SubtypeInfluenza A virusInfluenza B VirusInvestigational DrugsJointsLeadLung diseasesMedicalModelingMolecularMusOralOseltamivirPathogenesisPathogenicityPatientsPatternPharmaceutical PreparationsPharmacodynamicsPhospholipidsPilot ProjectsPolymerasePopulationPreparationProdrugsProductivityProgram DevelopmentProtocols documentationRecombinantsRecommendationReporterResistanceResistance profileRibonucleosidesRiskSeasonsStainsStructureStructure of parenchyma of lungStructure-Activity RelationshipTestingTherapeuticTissuesToxicologyTreatment EfficacyUnited StatesVaccinatedVaccinesViralViral Respiratory Tract InfectionVirusVirus DiseasesVirus InhibitorsWorkZoonosesanaloganti-influenzabaseclinical candidateclinical efficacyclinically significantdesigndrug developmentdrug discoveryexperiencehuman diseaseimprovedin vitro activityin vivoin vivo evaluationinfluenza virus straininfluenzavirusinhibitor/antagonistinnovationinsightmortalitymouse modelnovelnovel therapeuticspandemic diseasepandemic influenzapathogenpathogenic viruspatient populationpharmacokinetics and pharmacodynamicspre-clinicalpreclinical developmentprogramsprophylacticpyrimidine analogresearch clinical testingrespiratory virusscaffoldseasonal influenzaside effectsmall moleculestandard of caresynergismtherapeutic candidatetranscriptome sequencingtransmission processtripolyphosphateviral resistancezoonotic spillover
项目摘要
Summary
Influenza viruses are the leading cause of human disease due to respiratory viral infection worldwide. It is the
overarching objective of this partnership to advance a novel pyrimidine analog anti-influenza virus class
towards an investigational new drug-enabling package. The design of this program is driven by our underlying
hypothesis that effective next-generation therapeutics for the treatment of influenza must be orally available,
display a broad indication spectrum against influenza virus isolates of human, avian, and swine lineages, and
covers both influenza A (IAV) and B (IBV) viruses. These product profile demands are derived from the clinical
burden imposed by the diverse spectrum of seasonal influenza viruses, the pandemic potential arising from
spillover of zoonotic viruses into the human population, and current FDA recommendations that recognize non-
hospitalized adults suffering from seasonal influenza as the primary patient population for initial clinical testing.
These developmental objectives are best met with direct acting therapeutics, since host-targeted antiviral
therapies, although often tantalizingly broad in indication range, are prone to unacceptable side effects that are
incompatible with the primary patient group pursued.
Under the umbrella of a long-term academia/industry antiviral partnership, we have established a dual-
pathogen drug screening protocol that allows the simultaneous automated identification of target virus-specific
and broad-spectrum candidates. Implementation of this assay in a large-scale drug screening campaign has
yielded a cytidine analog with sub-micromolar antiviral potency. In pilot studies underpinning this preclinical
program, we have demonstrated that potent inhibitory activity extends to IAV and IBV isolates, covers viruses
representing human and zoonotic lineages, and includes highly pathogenic avian H5N1 and H7N9 viruses of
major pandemic threat. The lead compound is orally bioavailable, efficiently converted to the active
triphosphate in vivo, and showed sustained micromolar lung tissue concentrations. We have demonstrated oral
efficacy in mice against seasonal and highly pathogenic avian influenza viruses with pandemic potential and
observed substantial suppression of viral spread in the guinea pig IAV transmission model. In preparation of
clinical testing, this lead class will be subjected to mechanistic characterization and resistance profiling (aim 1).
In parallel, phospholipid prodrug formulations will be explored to boost drug tissue concentrations for severe
disease indications and a structurally independent alternative identified in our screen will be advanced through
chemical lead development for back-up to alleviate the potential risk of developmental failure (aim 2).
Pharmacokinetic and pharmacodynamic profiles of emerging phospholipid prodrug and back-up leads will be
generated and in vivo tolerability determined (aim 3). Efficacy of clinical candidates against seasonal and
highly-pathogenic viruses will be tested in mice and ferrets, the effect of prior drug exposure on pathogenesis
examined, and the impact on viral spreads assessed in guinea pigs (aim 4).
总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Richard K. Plemper其他文献
Cryo-Electron Tomography Provides Insight into the Native Architecture of the Measles Virus Assembly Site
冷冻电子断层扫描可深入了解麻疹病毒装配位点的原生结构
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:2.8
- 作者:
J. Strauss;Ke Zunlong;Richard K. Plemper;E. Wright - 通讯作者:
E. Wright
The Near-to-Native-State Architecture of Measles Virus Assembly Sites and Isolated Measles Virus Particles
麻疹病毒组装位点和分离的麻疹病毒颗粒的接近天然状态的结构
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:2.8
- 作者:
E. Wright;J. Strauss;Ke Zunlong;Cheri M. Hampton;Fredrick Leon;M. Brindley;Richard K. Plemper - 通讯作者:
Richard K. Plemper
Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity
ERDRP-0519 治疗麻疹病毒聚合酶可抑制所有 RNA 合成活性
- DOI:
10.1101/2020.09.23.311043 - 发表时间:
2020 - 期刊:
- 影响因子:6.7
- 作者:
R. Cox;Julien Sourimant;M. Govindarajan;M. Natchus;Richard K. Plemper - 通讯作者:
Richard K. Plemper
Capturing Enveloped Viruses on Affinity Grids for Downstream Cryo-Electron Tomography Applications
在亲和网格上捕获包膜病毒以用于下游冷冻电子断层扫描应用
- DOI:
10.1017/s1431927613002274 - 发表时间:
2013 - 期刊:
- 影响因子:2.8
- 作者:
Gabriella Kiss;Xuemin Chen;J. Holl;M. Brindley;P. Campbell;A. Lauren;Byrd;J. Steel;D. Steinhauer;C. Afonso;Richard K. Plemper;Paul;Spearman;Deborah F. Kelly;E. Wright - 通讯作者:
E. Wright
121 INTESTINAL MICROBIOME INFLUENCES SEVERITY OF RESPIRATORY VIRAL INFECTION VIA IMPACTING ALVEOLAR MACROPHAGES
- DOI:
10.1016/s0016-5085(23)01001-6 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:
- 作者:
Vu L. Ngo;Carolin M. Lieber;Richard K. Plemper;Andrew T. Gewirtz - 通讯作者:
Andrew T. Gewirtz
Richard K. Plemper的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Richard K. Plemper', 18)}}的其他基金
Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors
项目 1 — 口服生物可利用的 β-CoV 抑制剂的开发
- 批准号:
10513942 - 财政年份:2022
- 资助金额:
$ 97.96万 - 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
- 批准号:
10034283 - 财政年份:2020
- 资助金额:
$ 97.96万 - 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
- 批准号:
10666509 - 财政年份:2020
- 资助金额:
$ 97.96万 - 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
- 批准号:
10425285 - 财政年份:2020
- 资助金额:
$ 97.96万 - 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
- 批准号:
10199980 - 财政年份:2020
- 资助金额:
$ 97.96万 - 项目类别:
Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses
针对季节性和高致病性流感病毒的广谱抑制剂的开发
- 批准号:
10544324 - 财政年份:2019
- 资助金额:
$ 97.96万 - 项目类别:
Drug discovery against lyssaviruses by high thoughput screening
通过高通量筛选发现抗狂犬病病毒药物
- 批准号:
9218526 - 财政年份:2016
- 资助金额:
$ 97.96万 - 项目类别:
Identification and Hit-to-Lead Development of Influenza A Virus Inhibitors
甲型流感病毒抑制剂的鉴定和先导化合物开发
- 批准号:
8955538 - 财政年份:2015
- 资助金额:
$ 97.96万 - 项目类别:
Novel Therapeutics against Respiratory Syncytial Virus Infection
对抗呼吸道合胞病毒感染的新疗法
- 批准号:
8662435 - 财政年份:2014
- 资助金额:
$ 97.96万 - 项目类别:
Host-Directed Inhibitors of Myxovirus Replication
粘病毒复制的宿主定向抑制剂
- 批准号:
8566072 - 财政年份:2012
- 资助金额:
$ 97.96万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 97.96万 - 项目类别:
Research Grant