VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA.
Pharm Res. 2022 Nov;39(11):2937-2950. doi: 10.1007/s11095-022-03231-z. Epub 2022 Mar 21.
Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes.
Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions.
Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult.
Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.
代谢综合征关键信号通路的失调是多因素的，最终导致心血管事件。高血糖伴血脂异常导致胰岛素抵抗，并引发促炎细胞因子释放，导致慢性炎症、脂质过氧化加速，进而发展为动脉粥样硬化改变和糖尿病。我们提出了一种使用 FDA 批准的靶向 IL-17a 和 DPP4 的组合方法，以改善代谢综合征患者的大部分聚集临床风险。在我们目前的研究中，我们使用两种不同的药物类别来模拟代谢综合征的治疗结果。
根据代谢综合征的聚集临床风险选择靶点：血脂异常、胰岛素抵抗、葡萄糖控制受损和慢性炎症。使用 BIOiSIM™药物开发平台，针对两种具有不同作用模式和方式的不同药物类别进行筛选。对最有前途的药物进行药代动力学和药效学建模，展示组合治疗干预的预测结果。
初步研究表明，最有前途的药物属于 DPP-4 抑制剂和 IL-17A 抑制剂。埃格列汀被选为调节葡萄糖控制的候选药物，具有长期的减肥和改善血脂谱的附带益处。司库珠单抗是一种用于治疗银屑病的 IL-17A 封闭剂，被选为治疗继第一次代谢损伤后出现的一系列炎症性疾病的重新定位候选药物。
我们的分析表明，这种新型的诱导 DPP4 和 Il-17a 抑制的组合治疗方法很有可能改善代谢综合征中大部分聚集的临床风险。
