Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents

自噬调节剂作为新型广谱抗感染剂

• 批准号: 10573254
• 负责人: HERBERT W VIRGIN
• 金额: $ 738.13万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573254
• 关键词: Animal Model; Anti-Infective Agents; Antibiotics; Autophagocytosis; Award; BCL2 gene; Bacterial Infections; Biomedical Research; Biotechnology; Body part; Cell physiology; Chemicals; Chemistry; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Complex; Data; Development; Drug Controls; Drug Targeting; Drug resistance; Engineering; Equilibrium; Funding; Genes; Goals; Host Defense; Immunity; Immunology; Industry; Infection; Infection Control; Inflammation; Intervention; Knowledge; Letters; Medical; Medicine; Microbiology; Multiple Bacterial Drug Resistance; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Norovirus; Organism; Participant; Pathogenesis; Pathologic; Pathway interactions; Peptides; Pharmaceutical Preparations; Phylogenetic Analysis; Productivity; Proteins; Proteomics; Regulation; Research Personnel; Research Project Grants; Resistance; Resources; Risk; Role; Salmonella; Science; Series; System; Taxonomy; Technology; Therapeutic; Time; Toxin; Toxoplasma gondii; Translational Research; Tuberculosis; United States National Institutes of Health; Virus; Work; antimicrobial; antimicrobial resistant pathogen; cost; design; emerging pathogen; feasibility trial; improved; in vivo; infectious disease model; innovation; medical countermeasure; nanomolar; new outbreak; novel; novel strategies; pathogen; prevent; priority pathogen; programs; public health priorities; screening; small molecule; translational research program; whole genome

Program Summary – Overview: The goal of this Center of Excellence for Translational Research (CETR) Program is to develop host-directed broad-spectrum anti-infective agents against NIAID priority pathogens by targeting the autophagy pathway. The most common approach for treating infectious diseases is to target pathogen-encoded proteins. However, pathogens can evolve resistance, and the spectrum of many clinically used anti-infective agents is restricted to taxonomically-related organisms. The use of host-directed anti-infective therapies offers several potential advantages to treating infectious diseases; including (1) the ability to target taxonomically-diverse pathogens; (2) decreased potential for promoting the emergence of drug-resistant organisms; and (3) the possibility of developing single compounds that target multiple pathogens, thereby decreasing the financial and regulatory barriers for developing anti-infective agents. Moreover, broad-spectrum host-directed therapeutics, once approved for clinical use against more common agents (in which clinical trials are feasible), can be deployed for emerging pathogens, new outbreaks, and pathogens engineered with ill intent. Proof-of-principle of this approach – namely, the development of effective host-directed broad-spectrum anti-infective therapeutics – could have a dramatic impact on how we treat and prevent infectious diseases. In recent years, extensive data have emerged (from our group of CETR investigators and others) indicating that degradative autophagy and autophagy-related (ATG) gene-dependent functions in immunity are crucial in host defense against taxonomically diverse pathogens. Furthermore, we and others showed that autophagy augmentation is safe and beneficial in animal models of infectious diseases. Therefore, the development of compounds that enhance autophagy and ATG gene- dependent immunity represents an attractive strategy for host-directed broad-spectrum anti-infective therapeutics. This new application has evolved from a currently funded, highly successful CETR Program entitled “Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents”. The goal of both the currently funded Program and this new proposal is to generate autophagy pathway-directed compounds that are active against a range of taxonomically-unrelated pathogens (selected based on priority status and medical need). To accomplish our goals, we will pursue a strategy that advances our current therapeutic leads and validates new targets to expand our discovery pipeline. We will accomplish our goals through five research projects entitled: RP1: Targeting Beclin 1 complexes for broad-spectrum anti-infective therapeutics. RP2: Targeting genes and pathways for autophagy-dependent inhibition of bacterial infection. RP3: Targeting Atg gene-dependent immunity for novel anti-infective therapeutics. RP4: Harnessing autophagy to treat tuberculosis. RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins. PHS 398/2590 (Rev. 06/09) Page

计划摘要-概述：这个卓越的转化研究中心的目标 （CETR）计划是开发针对NIAID的宿主定向广谱抗感染药物 通过靶向自噬途径来优先治疗病原体。治疗感染性疾病最常用的方法 针对病原体编码的蛋白质。然而，病原体可以进化出耐药性， 许多临床上使用的抗感染剂的范围限于分类学上相关的生物体。使用 针对宿主的抗感染疗法为治疗感染性疾病提供了几个潜在的优势; 包括（1）靶向分类学上多样化的病原体的能力;（2）降低促进病原体的潜在能力。 耐药生物体的出现;以及（3）开发针对 多种病原体，从而减少开发抗感染药物的财政和监管障碍 剂.此外，广谱宿主导向疗法一旦被批准用于临床， 普通药剂（其中临床试验是可行的），可以用于新兴病原体，新的爆发， 和恶意制造的病原体这种方法的原则证明-即， 有效的宿主定向广谱抗感染疗法-可能对 如何治疗和预防传染病近年来，大量的数据已经出现（从我们的 一组CETR研究者和其他人）表明，降解性自噬和自噬相关（ATG） 免疫中的基因依赖性功能在宿主防御分类上不同的病原体中是至关重要的。 此外，我们和其他人表明，自噬增强在动物模型中是安全和有益的。 传染病因此，开发增强自噬和ATG基因的化合物- 依赖性免疫代表了针对宿主的广谱抗感染药物的有吸引力的策略， 治疗学这个新的应用程序是从目前资助的，非常成功的CETR计划发展而来的 标题为“Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents”。目前，双方的目标 资助的计划，这项新的建议是产生自噬途径导向的化合物， 针对一系列分类学上不相关的病原体（根据优先级状态和医疗需求选择）。到 为了实现我们的目标，我们将采取一项战略，推进我们目前的治疗领先地位，并验证新的 扩大我们的发现渠道我们将通过以下五个研究项目实现我们的目标： RP 1：靶向Beclin 1复合物用于广谱抗感染治疗。 RP 2：自噬依赖性抑制细菌感染的靶向基因和途径。 RP 3：靶向Atg基因依赖性免疫用于新型抗感染治疗。 RP 4：利用自噬治疗结核病 RP 5：自噬蛋白小分子探针的化学蛋白质组学发现。 PHS 398/2590（Rev.06/09）

项目成果

BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner.

BECN1F121A 突变增加了老年小鼠的自噬通量，并以器官依赖性方式改善了衰老表型。

• DOI: 10.1080/15548627.2022.2111852
• 发表时间: 2023
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Sebti,Salwa;Zou,Zhongju;Shiloh,MichaelU
• 通讯作者: Shiloh,MichaelU

Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1.

• DOI: 10.1021/jacs.2c08964
• 发表时间: 2022-10-12
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Tao, Yongfeng;Remillard, David;Vinogradova, Ekaterina V.;Yokoyama, Minoru;Banchenko, Sofia;Schwefel, David;Melillo, Bruno;Schreiber, Stuart L.;Zhang, Xiaoyu;Cravatt, Benjamin F.
• 通讯作者: Cravatt, Benjamin F.

pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis.

• DOI: 10.4049/jimmunol.2001363
• 发表时间: 2021-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Xie L;McKenzie CI;Qu X;Mu Y;Wang Q;Bing N;Naidoo K;Alam MJ;Yu D;Gong F;Ang C;Robert R;Marques FZ;Furlotte N;Hinds D;Gasser O;23andMe Research Team;Xavier RJ;Mackay CR
• 通讯作者: Mackay CR