HSP90 paralog selective small molecules as anti-old-world alpha-viral therapeutic leads.

HSP90 旁系同源选择性小分子作为抗旧世界 α 病毒治疗先导药物。

基本信息

批准号：
10753347
负责人：
Gaya K. Amarasinghe
金额：
$ 24.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753347
关键词：
Address Aedes Alphavirus Arboviruses Binding COVID-19 pandemic Chikungunya virus Classification Clinical Combined Modality Therapy Comparative Study Culicidae Data Development Disease Dose Emerging Communicable Diseases Endoplasmic Reticulum Exhibits Family Fever Frequencies Genes Genotype Geographic Locations Geography HSP 90 inhibition Health Heat-Shock Proteins 90 Human In Vitro Knowledge Lead Link Mayaro virus Metabolism Mitochondria Molecular Chaperones Mus Nonstructural Protein O&apos nyong-nyong virus Pharmaceutical Chemistry Phase Positioning Attribute Posture Predisposition Property Proteins Proteomics Recording of previous events Role Ross river virus Semliki forest virus Serum Solubility Structure-Activity Relationship Testing Therapeutic Togaviridae Toxic effect Universities Venezuelan Equine Encephalitis Virus Viral Viral Load result Viral Physiology Viremia Virion Virus Virus Diseases Washington Work analog chikungunya infection economic impact efficacious treatment in vivo indexing inhibitor innovation insight lead optimization novel novel therapeutics paralogous gene pharmacologic prophylactic response scaffold small molecule socioeconomics transmission process vector virology

项目摘要

COVID-19 pandemic highlights the impact of emerging infectious diseases and the global socioeconomic impact. Alphaviruses such as the chikungunya virus (CHIKV) has re-emerged along with many arthropod-borne viruses (arboviruses) and these viruses continue to pose a significant threat to global human health especially with recent vector expansion into non-endemic regions. CHIKV belongs to the Togaviridae family and is transmitted mainly by Aedes albopictus and Aedes aegypti mosquitose. The bent-up posture caused by CHIKV fever disease and the virus can be classified into three different lineages with distinct genotypes corresponding to their respective geographical origins. CHIKV infections cause high serum viral loads, and therefore, high viremia also contributes to rapid spread. Like other alphaviruses, there are no treatments for CHIKV and related viral infections. In recent exploratory studies, we have identified two inhibitors that inhibit CHIKV and related alphavirus Mayaro virus (MAYV). While prior studies have shown a potential role for HSP90 inhibitors, a major limitation associated with further development of HSP90 inhibitors is that pan-HSP90 activity results in toxicity. HSP90 family consists of 4 different paralogs, two cytosolic forms HSP90α (encoded by HSP90AA1), HSP90β (encoded by HSP90AB1 gene), Grp94, an endoplasmic reticulum resident HSP90 (encoded by HSP90B1) and mitochondrial Trap1. While pan-HSP90 activity provides the initial insights, they have many clinical liabilities. In our proposed studies, we will develop HSP90β specific inhibitors with reduced toxicity and enhanced efficacy as a host-directed anti- alphavirus therapeutic lead. We expect to move one or more scaffolds from hit-to-lead with selectivity index >200 and determine the mechanism of action (MOA). Collectively, we will fill a critical gap in the field.

COVID-19 大流行凸显了新发传染病的影响和全球社会经济影响。基孔肯雅病毒 (CHIKV) 等甲病毒与许多节肢动物传播的病毒一起重新出现（虫媒病毒），这些病毒继续对全球人类健康构成重大威胁，特别是最近 CHIKV 属于披膜病毒科，主要传播。由白纹伊蚊和埃及伊蚊引起的 CHIKV 热病和弯腰姿势。该病毒可分为三个不同的谱系，具有与其各自相对应的不同基因型 CHIKV 感染导致高血清病毒载量，因此高病毒血症也是造成这种情况的原因。与其他甲病毒一样，最近没有针对 CHIKV 和相关病毒感染的治疗方法。经过探索性研究，我们发现了两种抑制 CHIKV 和相关甲病毒 Mayaro 病毒的抑制剂 (MAYV)。虽然先前的研究已经显示了 HSP90 抑制剂的潜在作用，但与 HSP90抑制剂的进一步发展是泛HSP90活性导致了HSP90家族的毒性。 4 种不同的旁系同源物，两种胞质形式 HSP90α（由 HSP90AA1 编码）、HSP90β（由 HSP90AB1 编码）基因）、Grp94、内质网驻留 HSP90（由 HSP90B1 编码）和线粒体 Trap1。 pan-HSP90 活性提供了初步见解，在我们提出的研究中，它们有许多临床责任。将开发 HSP90β 特异性抑制剂，作为一种针对宿主的抗病毒药物，其毒性降低，功效增强。我们期望将一个或多个支架从命中转移到选择性指数>200的先导药物。并确定作用机制（MOA），我们将共同填补该领域的一个关键空白。