Small Molecular Inactivators of HIV

HIV 小分子灭活剂

• 批准号: 10919514
• 负责人: DANIEL H APPELLA
• 金额: $ 103.45万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10919514
• 关键词: Acetyl Coenzyme A; Acquired Immunodeficiency Syndrome; Biological Testing; Clinical; Collaborations; Drug Kinetics; Drug resistance; FDA approved; Female; Generations; HIV; HIV Infections; HIV resistance; HIV-1; Human; Lead; Lysine; Metabolism; Molecular; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Positioning Attribute; Process; Prodrugs; Proteins; Resistance development; Toxic effect; Translating; Vaccines; Variant; Viral; Viral Physiology; Virus; Virus Replication; Work; chemical synthesis; in vivo; male; microbicide; mortality; preclinical toxicity; prevent; resistant strain; scaffold; transacylation; transmission process

We have developed and studied our molecule both in the active form and as a prodrug. We have developed large-scale syntheses for these molecules and worked in collaboration to study their antiviral activity and evaluate their preclinical toxicity. Overall, the molecules show broad range of activity across a panel of HIV-1 clinical isolates in human PBMCs, demonstrate additive to synergistic antiviral interactions with other FDA-approved HIV drugs, and fail to allow the generation of HIV resistant strains after 14 passages. There is no observable toxicity with our molecules. Our molecules have also been successfully developed into platforms for application as a microbicide. The lead molecule has also been shown to work in combination with an experimental vaccine to enhance protection from HIV infection. We are currently examining the detailed mechanism of these molecules, performing an in vivo study, closely examining the pharmacokinetics and metabolism, and exploring whether these molecules have antiviral activity against other viruses.

我们已经开发和研究了我们的分子的活性形式和作为前药。我们已经开发了这些分子的大规模合成，并合作研究其抗病毒活性并评估其临床前毒性。总体而言，这些分子在人PBMC中的一组HIV-1临床分离株中显示出广泛的活性，证明了与其他FDA批准的HIV药物的协同抗病毒相互作用的相加作用，并且在14次传代后不能产生HIV耐药株。我们的分子没有明显的毒性。我们的分子也已成功开发成作为杀微生物剂应用的平台。这种先导分子也被证明可以与实验性疫苗结合使用，以增强对艾滋病毒感染的保护。我们目前正在研究这些分子的详细机制，进行体内研究，密切检查药代动力学和代谢，并探索这些分子是否对其他病毒具有抗病毒活性。

项目成果

Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus.

• DOI: 10.1016/j.antiviral.2016.08.022
• 发表时间: 2016-10
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Hartman TL;Yang L;Helfrick AN;Hassink M;Shank NI;George Rosenker K;Scerba MT;Saha M;Hughes E;Wang AQ;Xu X;Gupta P;Buckheit RW Jr;Appella DH
• 通讯作者: Appella DH

A novel preventive strategy against HIV-1 infection: combinatorial use of inhibitors targeting the nucleocapsid and fusion proteins.

• DOI: 10.1038/emi.2017.26
• 发表时间: 2017-06-07
• 期刊: Emerging microbes & infections
• 影响因子: 13.2
• 作者: Yang Y;Zhu J;Hassink M;Jenkins LMM;Wan Y;Appella DH;Xu J;Appella E;Zhang X
• 通讯作者: Zhang X