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New Inhibitors of HIV latency reactivation

HIV潜伏期再激活的新抑制剂

基本信息

批准号：
10208701
负责人：
JONATHAN KARN
金额：
$ 29.84万
依托单位：
ITHAX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-02 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208701
关键词：
Academia Advocate Affinity Animals Anti-Retroviral Agents Antiviral Agents Binding Biochemical Biological Assay Biological Models Biotechnology CD4 Positive T Lymphocytes Capital Cell Line Cell Membrane Permeability Cell model Cells Chemistry Complex DNA Polymerase II DNA-Directed RNA Polymerase Data Data Collection Development Disclosure Disease remission Drug Design Drug Kinetics Drug Targeting England Funding Genetic Transcription Goals Growth HIV HIV Genome In Vitro Industry Infection Lead Legal patent Licensing Modeling Molecular Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phosphotransferases Population Positioning Attribute Positive Transcriptional Elongation Factor B Privatization Property Proviruses RNA Regimen Reporting Rest Risk Safety Sales Series Small Business Innovation Research Grant Small Business Technology Transfer Research Structure Suspensions Technical Expertise Technology Therapeutic Agents Toxic effect Transcription Coactivator Transcription Elongation Treatment Protocols Universities Viral Viral Physiology Viremia Virus Virus Inhibitors Virus Latency Virus Replication Washington antiretroviral therapy base clinical investigation commercialization design drug discovery experience experimental study improved in vivo inhibitor/antagonist latent HIV reservoir memory CD4 T lymphocyte novel strategies pharmacokinetics and pharmacodynamics pre-clinical preclinical development premature prevent reactivation from latency recruit small molecule small molecule inhibitor tat Protein three dimensional structure virology

项目摘要

ABSTRACT Company - Ithax Pharmaceutical is a new spin-off biotechnology company, located in Seattle, focused on developing proprietary small molecule chemistry to target RNA. The experience of its founders spans virology, drug design and RNA structure and function, and gives it a unique technological expertise in the RNA-targeting space. Their commercial expertise includes the successful founding, and subsequent sale, of Ribotargets, an RNA-focused small molecule drug discovery company in Cambridge, England in 1997-2001. This Phase I STTR proposal lays out a series of experiments, beyond the scope of academic discovery, that are critical to advance and de-risk the commercialization and pharmaceutical plans of the company. Successful completion of this project will help Ithax improve the efficacy of exciting lead compounds, validate their activity in relevant primary cell model systems, and obtain ADME and PK/PD data. The resulting progress would facilitate its commercial growth by providing the data required to initiating the pre-clinical development of its lead small molecules under a subsequent phase II SBIR project, and the acquisition of the private capital required for IND-enabling studies that will follow. Technology – The existence of latent but replication competent viruses residing primarily in a very small population of resting memory CD4+ T cells limits the long term efficacy of anti-retroviral therapy because the virus inevitably rebounds once therapy is suspended. Escape from latency is driven by transcriptional reactivation of the HIV provirus, which requires stimulation of RNA Pol II processivity by the host P-TEFb kinase, which is recruited to the HIV TAR RNA through its interaction with the viral Tat protein, the only transcriptional activator encoded by the virus. It follows that inhibition of the Tat-TAR-P-TEFb complex would lead to suppression of viral reactivation and prevents the virus emergence from latency. This project furthers the development of a new class of small molecule inhibitors of Tat-TAR-P-TEFb discovered by the company’s founders that interact with TAR RNA and inhibit viral replication in cells. It will optimize the biochemical and cellular potency of the lead using structure-based drug design; assess the lead’s pharmacological properties in vitro and its in vivo pharmacokinetics and toxicity and evaluate its activity and mechanism of action in sophisticated cellular models of latency. Collection of these data will allow subsequent submission of a strong phase II SBIR project focused on pre-clinical investigations, and the parallel pursuit of private capital required for IND-enabling studies. 1

摘要