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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：
9914982
负责人：
Gregory William Henkel
金额：
$ 100万
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914982
关键词：
ABCB1 gene ABCG2 gene Acids Africa Anemia Animals Antiviral Agents 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 Detection 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 dosage experimental study in vivo infected vector rodent inhibitor/antagonist 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 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