Peptidomimetic Human SIRT1 Enzyme Inhibitors

拟肽人 SIRT1 酶抑制剂

基本信息

批准号：
7981333
负责人：
Weiping Zheng
金额：
$ 37.13万
依托单位：
UNIVERSITY OF AKRON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2011-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7981333
关键词：
Acetylation Acetyltransferase Active Sites Adopted Affinity Aging Amino Acids Animal Cancer Model Apoptosis Binding Biological Process Biology Biomedical Research Cell Membrane Permeability Cells Cellular Membrane Chemicals DNA Repair Deacetylase Deacetylation Development Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Exhibits Family Gene Expression Genetic Genetic Transcription Goals HIV-1 Human Laboratories Lead Ligand Binding Lysine Malignant Neoplasms Metabolism Molecular Molecular Conformation Nerve Degeneration Organic Synthesis Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Play Protein Acetylation Proteins Reaction Research Research Project Grants Role Screening procedure Side Solid Solutions Students Testing Time Training analog anti-cancer therapeutic base cancer therapy design implementation research inhibitor/antagonist interest mimetics next generation novel peptidomimetics protein aminoacid sequence public health relevance small molecule libraries three dimensional structure tool

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to develop a novel class of human SIRT1 inhibitors as potential treatment for cancer. Reversible protein acetylation plays critical roles in multiple important biological processes such as gene transcription, apoptosis, DNA repair, metabolism, aging, neurodegeneration, and HIV-1 replication. Protein deacetylation can be catalyzed by a class of evolutionarily conserved intracellular Sir2 family enzymes. In humans, seven Sir2 orthologues, i.e. SIRT1-7, have been identified. Interestingly, the gene expression and the deacetylase activity of SIRT1 are up-regulated in various human cancers. Pharmacological and genetic studies demonstrated that inhibition of the deacetylase activity of SIRT1 provides promising anti-cancer effect, which was further supported in studies on animal models of cancer. Therefore, SIRT1 deacetylase activity inhibition constitutes a novel anti-cancer therapeutic strategy. Even though several classes of SIRT1 inhibitors have been identified from efforts such as random chemical library screening, few of them exhibited potent and selective inhibitory profiles. There is thus an urgent need to develop new inhibitors for this important human enzyme. Based on the N?-thioacetyllysine-containing mechanism-based SIRT1 peptide inhibitor lead that has been identified in PI's laboratory, its macrocyclic peptidomimetic analogs will be synthesized and evaluated for their SIRT1 inhibitory potency and selectivity. Two different types of the peptide macrocycles will be incorporated into the designed peptidomimetic analogs. It is anticipated that potent and selective human SIRT1 inhibitor(s) will be identified from the completion of this proposed project. These compound(s) can also serve as the new lead for developing the next generation of human SIRT1 inhibitors as potential drugs for treating cancer. The identified compound(s) from the proposed project will also be valuable chemical tool(s) for further studying the SIRT1 biology. The implementation of this research project will create ample opportunities for training both graduate and undergraduate students in biomedical research. PUBLIC HEALTH RELEVANCE: The proposed project focuses on the development of the peptidomimetic human SIRT1 enzyme inhibitors. The proposed studies will help the development of novel anti-cancer therapeutics.

描述（由申请人提供）：这项拟议的研究的长期目标是开发一种新型的人类SIRT1抑制剂作为癌症的潜在治疗方法。可逆蛋白乙酰化在多种重要的生物学过程中起关键作用，例如基因转录，凋亡，DNA修复，代谢，衰老，神经变性和HIV-1复制。蛋白质脱乙酰化可以通过一类进化保守的细胞内SIR2家族酶催化。在人类中，已经确定了七个Sir2直系同源物，即SIRT1-7。有趣的是，在各种人类癌症中，SIRT1的基因表达和脱乙酰基酶活性被上调。药理学和遗传研究表明，SIRT1的脱乙酰基酶活性的抑制提供了有希望的抗癌作用，这在癌症动物模型的研究中得到了进一步的支持。因此，SIRT1脱乙酰基酶活性抑制是一种新型的抗癌治疗策略。即使已经从诸如随机化学库筛查之类的努力中确定了几类SIRT1抑制剂，但其中很少有有效和选择性的抑制作用。因此，迫切需要为这种重要的人类酶开发新的抑制剂。基于已在PI实验室中鉴定出的基于N？ - 硫代乙酰基机制的SIRT1肽抑制剂铅，将合成其大环肽类似类似物的SIRT1抑制作用和选择性。两种不同类型的肽大环将掺入设计的肽类似类似物中。预计将从该拟议项目的完成中确定有效和选择性的人类SIRT1抑制剂。这些化合物也可以作为开发下一代人SIRT1抑制剂作为治疗癌症的潜在药物的新铅。拟议项目的确定化合物也将是进一步研究SIRT1生物学的有价值的化学工具。该研究项目的实施将为培训生物医学研究的研究生和本科生提供足够的机会。公共卫生相关性：拟议的项目着重于肽型人类SIRT1酶抑制剂的发展。拟议的研究将有助于开发新的抗癌治疗剂。