PDF(Pubmed)
Abstract：
The NAD+-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor YZL-51N. We initially isolated bioactive YZL-51N from cockroach (Periplaneta americana) extracts and then developed the de novo synthesis of this compound. Further investigation revealed that YZL-51N impaired SIRT7 enzymatic activities through occupation of the NAD+ binding pocket. YZL-51N attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified YZL-51N as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
摘要：
NAD+依赖性脱乙酰酶SIRT7是DNA损伤反应（DDR）的关键调节因子，也是开发癌症疗法的有希望的药物靶标。然而,在SIRT7调制器发现方面取得了有限的进展。这里,我们应用基于肽的脱乙酰酶平台进行SIRT7酶促评估，并成功鉴定出一种有效的SIRT7抑制剂YZL-51N。我们最初从蟑螂（美洲大猩猩）提取物中分离出生物活性YZL-51N，然后开发了该化合物的从头合成。进一步的研究表明，YZL-51N通过占据NAD结合袋而损害了SIRT7的酶活性。YZL-51N减弱了电离辐射（IR）在结直肠癌细胞中诱导的DNA损伤修复，并与依托泊苷联合使用时表现出协同抗癌作用。总的来说,我们的研究不仅从昆虫资源中鉴定出YZL-51N为选择性SIRT7抑制剂，但也证实了其通过干扰DNA损伤修复过程在联合化学放疗中的潜在用途。
