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Validation and characterization of Tat inhibitors identified through HTS

通过 HTS 鉴定的 Tat 抑制剂的验证和表征

基本信息

批准号：
10468812
负责人：
Susana T Valente
金额：
$ 23.13万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-12 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468812
关键词：
Affinity Animal Model Anti-HIV Agents Anti-Retroviral Agents Apical Apoptosis Automobile Driving Biochemical Biological Assay CD4 Positive T Lymphocytes Calorimetry Cell Line Cell model Cells Chemicals Chimeric Proteins Clinical Clinical Trials Collaborations Complement Complex Confocal Microscopy DNA Development Disease remission Electrophoretic Mobility Shift Assay Epigenetic Process Feedback Fluorescence Future Gene Silencing Genetic Transcription Genome Goals HIV HIV-1 Hela Cells Human In Vitro Individual Interruption Lead Letters Luciferases Metabolic Modification Molecular Computations Neurotransmitters Nuclear Oxidative Stress Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacology Phase Production Property Proviruses RNA Research Role Structure Structure-Activity Relationship Sum System TNF gene Techniques Testing Tetanus Helper Peptide Therapeutic Intervention Titrations Toxic effect Transactivation Transcript Triage Tryptophan Validation Viral Viral Proteins Viral reservoir Virus Virus Replication analog antiretroviral therapy base blood-brain barrier disruption chemical synthesis chromatin immunoprecipitation clinical candidate cortistatin cost cost effective counterscreen cytotoxicity detection limit drug development follow-up high throughput screening high-throughput drug screening humanized mouse in vitro testing indexing inhibitor interest molecular dynamics mouse model neuroinflammation neurotoxicity novel novel drug class novel strategies particle pre-clinical promoter scaffold small molecule success targeted treatment tat Protein viral rebound viral resistance

项目摘要

ABSTRACT Despite effective antiretroviral therapy (ART), latent proviruses can reinitiate viral production upon cell stimulation or treatment interruption. The viral Tat protein enhances transcript elongation from the HIV-1 promoter, controlling the switch between latency and active viral production. The block-and-lock functional cure aims at the transcriptional silencing of the viral reservoir rendering suppressed HIV promoters extremely difficult to reactivate from latency. The Tat inhibitor, didehydro-cortistatin A (dCA) was used to prove this concept. Combining dCA with ART, inhibits transcription and blocks viral rebound upon treatment interruption, as the promoter becomes epigenetically repressed. dCA defines a novel class of drugs that can silence and maintain a transcriptionally inactive HIV promoter, offering a novel approach in the treatment of HIV. Tat is very attractive target for therapeutic intervention because: 1) is expressed early during virus replication; 2) no cellular homologs; 3) Tat inhibitors block the feedback loop necessary for viral amplification; 4) epigenetic modifications accumulate at the HIV promoter rendering reactivation less likely. Tat is also known for its role in neurotoxicity, neurotransmitter modulation, oxidative stress, apoptosis, blood brain barrier disruption, and neuroinflammation. Thus, the immense interest in the development of Tat inhibitors to complement ART. The major hurdle towards advancing dCA into clinical trials is the cost of producing large quantities of this molecule, due to its complex structure. Additional clinical candidates, structurally distinct from dCA, that embody equivalent bioactivity are needed in the pre-clinical pipeline. We optimized a cell-based Tat transactivation assay to use in high throughput screening (HTS), with dCA as control. We combined appropriate counter-screens and a wealth of techniques to quickly ‘weed out’ small molecules that are not Tat specific. The HTS of 210,240 compounds was completed by Southern Research (SR), yielding two compounds, SRI-43627 and SRI-43050 with a selectivity index >10 that were further investigated. This initial success prompted the screen of an additional 369,203 compounds, yielding upon counter screen 29 hits to be further evaluated. In this application, we propose to perform hit validation and characterization of these compounds as well as analogs synthesized by SR as part of drug development during the compound progression pathway. We propose the following aims: Specific Aim 1. Validate Tat inhibitors based on disruption of Tat HIV-1 LTR transactivation. Specific Aim 2. Characterize the mechanism of action of selected hits. At the end of this study we expect to (a) have identified small molecules that will specifically inhibit Tat in cell-based assays. (b) have adequate metabolic stability and PK properties for future pharmacological assessment in animal models and eventually in human clinical trials.

摘要

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Forging a Functional Cure for HIV: Transcription Regulators and Inhibitors.

DOI：
10.3390/v14091980
发表时间：
2022-09-07
期刊：
Viruses
影响因子：
0
作者：
Mediouni S;Lyu S;Schader SM;Valente ST
通讯作者：
Valente ST

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Susana T Valente其他文献

Potent suppression of HIV viral replication by a novel inhibitor of Tat

DOI：
10.1186/1742-4690-9-s1-o11
发表时间：
2012-05-25
期刊：
Retrovirology
影响因子：
3.900
作者：
Guillaume Mousseau;Mark A Clementz;Wendy N Bakeman;Nisha Nagarsheth;Michael Cameron;Jun Shi;Phil Baran;Rémi Fromentin;Nicolas Chomont;Susana T Valente
通讯作者：
Susana T Valente