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Pre-IND Development of an Arenavirus Antiviral

沙粒病毒抗病毒药物的 IND 前开发

基本信息

批准号：
10357791
负责人：
Gregory William Henkel
金额：
$ 99.73万
依托单位：
ARISAN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-10 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357791
关键词：
ABCB1 gene ABCG2 gene Acids Africa Anemia Animals Arenavirus Arenavirus Infections Argentinian Hemorrhagic Fever Binding Proteins Canis familiaris Cardiac Case Fatality Rates Category A pathogen Cavia Cell Line Cells Chemicals Chemistry Chinese Hamster Ovary Cell Chromosome abnormality Clinical Clinical Pathology Crystallization Development Dose Engineering Enzymes Equilibrium Evaluation Excipients Excretory function Exhibits FDA approved Family Formulation G-Protein-Coupled Receptors Geography Glycoproteins Goals Healthcare Systems High Pressure Liquid Chromatography Human In Vitro Infection Intestines Ion Channel Junin virus Liquid substance Liver Extract Manuals Maximum Tolerated Dose Methods Modeling Morbidity - disease rate No-Observed-Adverse-Effect Level Old World Arenaviruses Oral Organic solvent product Outcome Particle Size Pathogenicity Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Polymorph Preventive vaccine Process Rattus Recovery Ribavirin Running Safety Series Serum Sodium Chloride Solid Solubility Solvents Stomach Survivors Suspensions Tablets Testing Therapeutic Therapeutic Index Thrombocytopenia Time Toxic effect Toxicokinetics Toxicology Transplantation Vaccines Vesicular stomatitis Indiana virus Viral Hemorrhagic Fevers Visual Zoonoses analytical method aqueous base capsule detection limit dosage experimental study in vivo infected vector rodent inhibitor lead candidate method development mortality nanomolar neurobehavioral novel novel therapeutics patch clamp pathogen pre-clinical preclinical study prophylactic safety study scale up screening side effect surfactant transmission process vaccine access weapons

项目摘要

Summary Arenaviruses comprise a diverse family. Several species are associated with severe arenaviral hemorrhagic fever (AVHF) in humans that exhibit case-fatality rates as high as 30%. Human infection with arenaviruses typically occurs through contact with materials contaminated with the excretions of an infected rodent although direct human- to-human transmission may occur in clinical settings. AVHF resulting from infection with the Old World arenavirus Lassa is estimated to cause over 300,000 annual infections in Africa, of which 15-20% of hospitalized patients die while survivors often suffer permanent sequelae. Similar outcomes are observed with Argentine hemorrhagic fever (AHF), caused by infection with Junin virus. A prophylactic vaccine has been developed against JUNV, however, no vaccines are available against Lassa or the other human hemorrhagic fever arenaviruses and broad-spectrum vaccines effective against both current and emerging arenaviruses are unlikely to be developed. Ribavirin, the only available antiviral, can be effective in treating arenavirus infection (particularly with IV administration in the first 6 days), however, there are serious side effects including thrombocytopenia and anemia. Given the limited treatment and prophylactic options, the high mortality rate, the potential for both zoonotic and human-to-human transmission, and the potential for geographical transplantation and bio- weaponization six arenaviruses have been recognized as Category A pathogens. W e have identified a novel chemical series of entry inhibitors including drug-like candidate compounds with sub-nanomolar, broad spectrum arenavirus activity, which exhibit remarkable in vivo efficacy. Here we propose Phase IIb studies to provide IND-enabling studies of the lead candidate, including CMC, API process chemistry and scale up as well as in vitro and in vivo toxicity and safety studies.

总结沙粒病毒包括一个不同的家庭。几个物种与严重的人类的沙粒病毒性出血热（AVHF），其病死率高达百分之三十人感染沙粒病毒通常通过接触材料发生被受感染啮齿动物的排泄物污染，尽管是直接的人与人之间的感染，传播可能发生在临床环境中。老年人感染引起的AVHF 世界沙粒病毒拉沙估计每年在非洲造成30多万人感染， 15-20%的住院患者死亡，而幸存者往往遭受永久性的后遗症阿根廷出血热（AHF）也有类似的结果，感染了朱宁病毒已经开发了针对JUNV的预防性疫苗，然而，没有针对拉沙或其他人类出血热的疫苗沙粒病毒和广谱疫苗，有效对抗当前和新出现的沙粒病毒不太可能被开发出来。利巴韦林是唯一可用的抗病毒药物，有效治疗沙粒病毒感染（特别是在前6个月内IV给药）然而，有严重的副作用，包括血小板减少和贫血。给定有限的治疗和预防选择，高死亡率，人畜共患病和人传人，以及地理传播的可能性。移植和生物武器化六种沙粒病毒被认为是 A类病原体。我们已经确定了一个新的化学系列的进入抑制剂，包括具有亚纳摩尔、广谱沙粒病毒活性的药物样候选化合物，其显示出显著的体内功效。在此，我们建议开展IIb期研究，先导候选药物的IND启动研究，包括CMC、API工艺化学和规模放大以及体外和体内毒性和安全性研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors.

DOI：
10.1016/j.bmcl.2021.127983
发表时间：
2021-06-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Plewe, Michael B.;Gantla, Vidyasagar Reddy;Sokolova, Nadezda, V;Shin, Young-Jun;Naik, Shibani;Brown, Eric R.;Fetsko, Alexandra;Zhang, Lihong;Kalveram, Birte;Freiberg, Alexander N.;Henkel, Greg;McCormack, Ken
通讯作者：
McCormack, Ken

Potent inhibition of arenavirus infection by a novel fusion inhibitor.

DOI：
10.1016/j.antiviral.2021.105125
发表时间：
2021-09
期刊：
Antiviral research
影响因子：
7.6
作者：
Gowen BB;Naik S;Westover JB;Brown ER;Gantla VR;Fetsko A;Dagley AL;Blotter DJ;Anderson N;McCormack K;Henkel G
通讯作者：
Henkel G

Severe mammarenaviral disease in guinea pigs effectively treated by an orally bioavailable fusion inhibitor, alone or in combination with favipiravir.