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种新型的人类SIRT 1抑制剂，作为癌症的潜在治疗方法。可逆的蛋白质乙酰化在基因转录、细胞凋亡、DNA修复、代谢、衰老、神经变性和HIV-1复制等多种重要的生物学过程中起着关键作用。蛋白质脱乙酰化可以由一类进化上保守的细胞内Sir 2家族酶催化。在人类中，已经鉴定了七种Sir 2直向同源物，即SIRT 1 -7。有趣的是，SIRT 1的基因表达和脱乙酰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SIRT 1的脱乙酰酶活性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，SIRT 1脱乙酰酶活性抑制构成了一种新的抗癌治疗策略。尽管已经从诸如随机化学文库筛选的努力中鉴定了几类SIRT 1抑制剂，但它们中很少有表现出有效的和选择性的抑制谱。因此，迫切需要为这种重要的人类酶开发新的抑制剂。根据N？PI的实验室中已经鉴定了基于硫代乙酰基赖氨酸机制的SIRT 1肽抑制剂先导化合物，将合成其大环肽模拟物类似物并评估其SIRT 1抑制效力和选择性。将两种不同类型的肽大环化合物掺入所设计的拟肽类似物中。预计在完成本拟定项目后，将鉴定出强效和选择性人SIRT 1抑制剂。这些化合物也可以作为开发下一代人类SIRT 1抑制剂的新先导，作为治疗癌症的潜在药物。从拟议项目中鉴定出的化合物也将是进一步研究SIRT 1生物学的有价值的化学工具。该研究项目的实施将为生物医学研究的研究生和本科生的培训创造充足的机会。 公共卫生相关性：拟议项目的重点是开发拟肽人类SIRT 1酶抑制剂。拟议的研究将有助于新型抗癌疗法的开发。

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.