Peptidomimetic Human SIRT1 Enzyme Inhibitors

描述（由申请人提供）：这项拟议研究的长期目标是开发一类新的人类SIRT1抑制剂作为癌症的潜在治疗方法。可逆蛋白乙酰化在基因转录、细胞凋亡、DNA修复、代谢、衰老、神经变性和HIV-1复制等多个重要的生物学过程中起着至关重要的作用。蛋白质去乙酰化可以由一类进化上保守的细胞内Sir2家族酶催化。在人类中，已鉴定出7个sirr2同源基因，即SIRT1-7。有趣的是，SIRT1的基因表达和去乙酰化酶活性在各种人类癌症中上调。药理学和遗传学研究表明，抑制SIRT1的去乙酰化酶活性具有良好的抗癌作用，这在癌症动物模型研究中得到了进一步的支持。因此，抑制SIRT1去乙酰化酶活性是一种新的抗癌治疗策略。尽管通过随机化学文库筛选已经确定了几种SIRT1抑制剂，但它们中很少有表现出有效和选择性的抑制特征。因此，迫切需要为这种重要的人类酶开发新的抑制剂。基于N？-硫代乙酰赖氨酸-含机制的SIRT1肽抑制剂铅，已在PI实验室鉴定，其大环肽模拟类似物将被合成并评估其SIRT1抑制效力和选择性。两种不同类型的肽大环将被纳入设计的拟肽类似物中。预计该项目完成后将发现有效的、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类SIRT1抑制剂作为治疗癌症的潜在药物的新先导。该项目所鉴定的化合物也将为进一步研究SIRT1生物学提供有价值的化学工具。本研究计划的实施将为培养生物医学研究的研究生和本科生创造充足的机会。

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.