School of Bioengineering, Dalian University of Technology, Dalian 116024, China.
College of Life Science, Dalian Minzu University, Dalian 116600, China.
Molecules. 2024 Jan 31;29(3):670. doi: 10.3390/molecules29030670.
Protein tyrosine phosphatases (PTPs) are ubiquitous in living organisms and are promising drug targets for cancer, diabetes/obesity, and autoimmune disorders. In this study, a histone deacetylase inhibitor called suberoylanilide hydroxamic acid (SAHA) was added to a culture of marine fungi ( DL1045) to identify potential drug candidates related to PTP inhibition. Then, the profile of the induced metabolites was characterized using an integrated metabolomics strategy. In total, 46% of the total SMs were regulated secondary metabolites (SMs), among which 20 newly biosynthesized metabolites (10% of the total SMs) were identified only in chemical epigenetic regulation (CER) broth. One was identified as a novel compound, and fourteen compounds were identified from first. SAHA derivatives were also biotransformed by DL1045, and five of these derivatives were identified. Based on the bioassay, some of the newly synthesized metabolites exhibited inhibitory effects on PTPs. The novel compound sydowimide A (A11) inhibited Src homology region 2 domain-containing phosphatase-1 (SHP1), T-cell protein tyrosine phosphatase (TCPTP) and leukocyte common antigen (CD45), with IC values of 1.5, 2.4 and 18.83 μM, respectively. Diorcinol (A3) displayed the strongest inhibitory effect on SHP1, with an IC value of 0.96 μM. The structure-activity relationship analysis and docking studies of A3 analogs indicated that the substitution of the carboxyl group reduced the activity of A3. Research has demonstrated that CER positively impacts changes in the secondary metabolic patterns of DL1045. The compounds produced through this approach will provide valuable insights for the creation and advancement of novel drug candidates related to PTP inhibition.
蛋白酪氨酸磷酸酶（PTPs）在生物体内普遍存在，是癌症、糖尿病/肥胖症和自身免疫性疾病的有希望的药物靶点。在这项研究中，向海洋真菌（DL1045）的培养物中添加了一种组蛋白去乙酰化酶抑制剂，即丁烯二酰苯胺羟肟酸（SAHA），以鉴定与 PTP 抑制相关的潜在药物候选物。然后，使用综合代谢组学策略对诱导代谢物的特征进行了描述。在总共 46%的总 SM 中，有 20 种新生物合成的代谢物（占总 SM 的 10%）仅在化学表观遗传调控（CER）培养基中被鉴定出来。一种被鉴定为新化合物，有 14 种化合物是从第一组被鉴定出来的。SAHA 衍生物也被 DL1045 生物转化，其中 5 种衍生物被鉴定出来。基于生物测定，一些新合成的代谢物对 PTPs 表现出抑制作用。新化合物 sydowimide A（A11）抑制Src 同源结构域 2 区磷酸酶-1（SHP1）、T 细胞蛋白酪氨酸磷酸酶（TCPTP）和白细胞共同抗原（CD45），IC 值分别为 1.5、2.4 和 18.83 μM。Diorcinol（A3）对 SHP1 的抑制作用最强，IC 值为 0.96 μM。A3 类似物的结构-活性关系分析和对接研究表明，羧基的取代降低了 A3 的活性。研究表明，CER 对 DL1045 次生代谢模式的变化有积极影响。通过这种方法产生的化合物将为创造和推进与 PTP 抑制相关的新型药物候选物提供有价值的见解。
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