新型糖苷类衍生物降糖作用筛选和研究

目的 针对钠-葡萄糖协同转运蛋白抑制剂（SGLT）靶点,通过尿糖检测方法筛选和评价糖苷类衍生物的降糖作用。方法 SD大鼠分别单次ig给予8个新型糖苷类衍生物30 mg/kg,在不同时段收集大鼠的尿液,己糖激酶法测定葡萄糖的量;尾静脉取血,血糖仪测血糖水平;同时对活性化合物进行大鼠糖耐量实验。结果 新型糖苷类衍生物中N-糖苷类化合物TY702-1N和S-糖苷类化合物TY702-1S对大鼠ig葡萄糖水溶液后的排糖作用较弱,C-糖苷类化合物TY702-4C的排糖作用较强,且显示剂量相关性。结论 就开发和研制作用强、药动学性质好的降糖药物而言,新型糖苷类衍生物TY702-4C是一个具有较好前景的先导化合物。     

钠-葡萄糖协同转运蛋白2抑制剂对心血管系统影响的研究进展

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一类新型的抗高血糖药物,该药通过抑制肾小管上皮细胞SGLT2的功能以减少尿中葡萄糖的重吸收,从而达到降低血糖的目的。该药除了降血糖,还具有降低血压、体质量及尿酸水平,改善血脂异常等心血管危险因素的作用,对心血管系统有较好的保护作用,且不良反应小、安全可靠。该类药物在国外上市以来受到广泛关注,随着对药物研究的深入,其作用机制及不良反应也越来越明确,应用也将越来越广泛。     

连翘苷D和凝血因子Xa相互作用的分子动力学模拟

目的 阐明连翘苷 D (FTD) 与凝血因子 Xa (FXa) 活性位点的动态相互作用过程，为设计新药提供参考依据。方法 利用 FXa 蛋白与其原始配体 (RPR) 的合理复合物结构作参照物，通过对接获得了 FTD 与 FXa 的复合结构。采用分子动力学方法模拟了两个复合物在水溶液中 500 ps 运动轨迹，考察配体与受体在动态相互作用过程中的变化过程。结果 RPR 依靠氢键作用与受体 S1 区域和中间部保持稳定的匹配状态，以非极性的芳香基与 S4 区域 (Tyr99、Phe174、Trp215) 形成了很好的空间匹配。FTD 与受体相互作用方式不同，与受体的 S1 区域作用较弱，相对而言与 S4 区域及中间部的作用较强，导致在相互作用的过程中被受体排斥出来。结论 通过配体与受体动态相互作用模拟研究表明，作为 FXa 的抑制剂与受体 S1 区结合的部分结构应该相对刚性，能与受体形成较强的氢键，在 S4 区需要一定的疏水性和芳香性，在中间部分需要一定量的氢键来帮助固定配体。     

新型抗2型糖尿病药物钠-葡萄糖协同转运蛋白2抑制剂研究进展

钠-葡萄糖协同转运蛋白(SGLT)是一类位于小肠黏膜(SGLT1)和肾近曲小管(SGLT2和SGLT1)中的葡萄糖转运基因家族.其中,SGLT2是一种低亲和力的转运蛋白,在肾脏中特异性表达并且在近曲小管葡萄糖重吸收中发挥非常重要的作用.它可以选择性地抑制SGLT2,即可通过增加尿糖的排出来治疗2型糖尿病,是一种创造性的...     

SGLT2抑制剂药物的研究进展

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一种能够特异性抑制肾小球近端小管,对滤过葡萄糖重吸收,使过量的葡萄糖从尿液中排出,直接降低血糖的药物。目前临床研究表明,SGLT2抑制剂具有良好的药效、安全性和耐受性,能够有效地降低血糖,增加尿液中葡萄糖的排出量,可能成为一种新的治疗2型糖尿病(T2DM)高血糖的方法。现就SGLT2抑制剂在T2DM治疗方面的最新研究进展予以综述。     

钠-葡萄糖共转运蛋白2抑制剂治疗心力衰竭的临床研究进展

钠-葡萄糖协同转运蛋白2 (SGLT2).抑制剂是最新一类治疗2型糖尿病(T2DM)的非胰岛素依赖型药物.在随机对照研究和大型真实临床应用分析中均显示SGLT2抑制剂能降低T2DM患者的心力衰竭住院和心血管死亡风险,且患者的心血管获益并不依赖于降糖效应.最新针对伴或不伴T2DM的心力衰竭患者(左心室射血分数小于或等于40％)的研究发现,SGLT2抑制剂显著改善心力衰竭再住院风险或心血管死亡等心血管结局事件.此外,SGLT2抑制剂的安全性也在临床应用中被逐渐证实.总之,SGLT2抑制剂正在从单纯的降糖药物向兼具降糖和治疗心衰的双重身份转变,现就SGLT2抑制剂治疗心力衰竭的临床研究进行综述.     

钠-葡萄糖协同转运蛋白2抑制剂对糖尿病肾病保护机制的研究进展

 糖尿病肾病(diabetic kidney disease, DKD)是导致终末期肾病(end-stage renal disease, ESRD)的主要原因,其防治是目前临床和基础研究的热点与重点。钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporter 2, SGLT2)抑制剂是一种新型降糖药物,除了降糖作用以外,还有肾脏保护作用,其机制可能包括降低血糖、改善肾脏血流动力学稳态、减轻氧化应激、减少肾小管间质损伤、抑制肾脏炎症及纤维化和降低尿酸水平等。本文就SGLT2抑制剂对DKD保护机制的研究进展作一综述。     

钠-葡萄糖转运蛋白2的同源模建研究

钠-葡萄糖转运蛋白2(SGLT2)是一类介导肾脏葡萄糖重吸收的葡萄糖转运蛋白,其抑制剂可减少葡萄糖的重吸收,促进尿液中葡萄糖的排泄,有效降低血糖水平,被认为是糖尿病治疗的新靶点。目前尚无可用的SGLT2晶体结构,这极大地限制了从天然活性物质中筛选和开发SGLT2抑制剂。运用计算机辅助药物设计的方法,通过同源模建对SGLT2的三维结构进行模拟,采用拉氏图、分子对接以及与实验活性对比等方法对模型质量进行评估。结果表明,所构建的SGLT2三维模型合理、可靠,可用于开展基于结构的虚拟筛选,或为开发新型、高效、安全的非糖苷类SGLT2抑制剂提供参考。     

Dapagliflozin-糖尿病治疗的模式转变

Dapagliflozin在治疗2型糖尿病的临床前期和临床期研究表明,钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂增加肾糖排泄,可以降低血糖以及减轻体质量。大型试验论证了Dapagliflozin可能产生良好的效果而不出现重大不良反应,说明其具有安全性和有效性。因此,这类药物具有超过目前使用的许多降糖药的优势。现就SGLT2在糖代谢方面的作用和目前Dapagliflozin在治疗糖尿病中的应用进行综述。     

光谱法研究槲皮苷与人血清白蛋白的相互作用

目的 研究槲皮苷与人血清白蛋白（HSA）的相互作用,并探讨葡萄糖对二者结合的影响。方法 应用光谱法研究槲皮苷与HSA的作用机制,以双对数方程和能量转移原理计算槲皮苷与HSA的结合常数、结合位点数和结合距离;根据热力学参数判断二者的作用力类型;用同步荧光光谱考察槲皮苷对HSA构象的影响;观察葡萄糖浓度对反应结合常数和结合位点数的影响。结果 槲皮苷对HSA的荧光猝灭过程为生成复合物的静态猝灭;结合常数和结合位点数随温度的升高而降低;结合距离小于7 nm;二者主要以疏水作用力相结合;槲皮苷与HSA的相互作用改变了色氨酸残基所处的微环境;葡萄糖的加入使结合常数和结合位点数均增加。结论 槲皮苷能与HSA结合并改变HSA的构象,生理浓度的葡萄糖可增加槲皮苷与HSA的结合常数和结合位点数。     

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

The papain-like protease (PL^pro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL^pro, which can be further developed as potential pan-PL^pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL^pro were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL^pro, and showed consistent interaction profile with SARS-CoV PL^pro and MERS-CoV PL^pro as well. Conclusively, the reported SARS-CoV-2 PL^pro specific compounds could serve as seeds for developing potent pan-PL^pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.     

Efficacy and Safety of SGLT2 Inhibitors in Patients with Type 1 Diabetes: A Meta-analysis of Randomized Controlled Trials

Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2 (SGLT2) inhibitor—SGLT2 inhibitors, in combination with insulin for type 1 diabetes mellitus (T1DM). Methods We searched Medline, Embase, and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration (FDA) data and ClinicalTrials (http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria: randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin (HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin, and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items: fasting blood glucose, HbA1c, glycosuria, or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3. Results Three trials including 178 patients were enrolled. As compared to the placebo group, SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences(MD)?2.47 mmol/L, 95% confidence interval (CI)?3.65 to?1.28,P<0.001] and insulin dosage (standardized MD?0.75 U, 95%CI?1.17 to?0.33,P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose (MD 131.09 g/24 h, 95%CI91.79 to 170.39,P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio (OR) 1.82, 95%CI 0.63 to 5.29,P=0.27], urinary tract infection (OR 0.95, 95%CI 0.19 to 4.85, P=0.95), genital tract infection (OR 0.27, 95%CI 0.01 to 7.19,P=0.43), and diabetic ketoacidosis (OR6.03, 95%CI 0.27 to 135.99,P=0.26) between the two groups. Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.     

Effects of DAPAgliflozin on CARDiac substrate uptake,myocardial efficiency,and myocardial contractile work in type 2 diabetes patients—a description of the DAPACARD study

Abstract

Background: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels.

Methods: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6?weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET).

Conclusion: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.     

钠-葡萄糖转运体2抑制剂辅助治疗成年人1型糖尿病的研究进展

1型糖尿病（T1DM）严重危害人们的健康和生命,但其经胰岛素降糖治疗后血糖达标率普遍偏低。长期使用胰岛素可导致频发低血糖、体质量增加和血压上升,进一步增加T1DM患者心血管事件发生风险。有研究显示新型降糖药物钠-葡萄糖转运体2（SGLT2）抑制剂辅助胰岛素治疗成年人T1DM可在减少胰岛素用量的同时进一步降低血糖,且不增加严重低血糖发生风险;但也有研究报道SGLT2抑制剂可增加成年T1DM患者糖尿病酮症酸中毒（DKA）发生风险。因此找到SGLT2抑制剂用于成年人T1DM的获益与风险的平衡点是临床研究的关键。本文汇总了近几年更新的关于SGLT2抑制剂用于成年人T1DM治疗的重要研究结果,对SGLT2抑制剂辅助胰岛素治疗成年人T1DM的获益与风险进行综述,以期为临床应用和未来研究提供参考。     

恩格列净与DDP4抑制剂治疗2型糖尿病疗效比较的Meta分析

目的 系统性评价恩格列净与DDP4抑制剂治疗2型糖尿病疗效比较。方法 计算机检索PubMed、Embase、Cochrane图书馆、the ISI Web of Knowledge Databases、VIP、CNKI、CBM和万方数据库,查找所有比较恩格列净和DDP4抑制剂2型糖尿病的随机对照试验（RCT）,检索时限均为建库至2016年3月28日。同时手检纳入文献的参考文献,按纳入排除标准由2人独立进行RCT的筛选、资料提取和质量评价后,采用RevMan 5.1软件进行Meta分析,并采用Cochrane系统评价的办法评价纳入研究质量。结果 纳入符合标准的随机对照试验5例,共计患者1935例。Meta分析结果显示,在有效性方面：与DDP4抑制剂（利拉西汀、西格列汀）相比,两组降低糖化血红蛋白相似（MD=-0.07,95%CI：-0.13~-0.01,P < 0.05）、恩格列净组空腹血糖明显降低（MD=-16.73,95%CI：-21.02~-12.43,P < 0.01）、体重减轻（MD=-2.43,95%CI：-2.68~-2.19,P < 0.01）。在安全性方面,两组间低血糖发生率相似,差异无统计学意义（OR=0.86,95%CI：0.46~1.6,P > 0.05）、恩格列净组生殖系统感染发生率明显增高,差异有统计学意义（OR=2.85,95%CI：1.71~4.76,P < 0.01）。结论 恩格列净组与DDP4抑制剂组相比,能够明显降低空腹血糖、体重,但生殖系统感染率增高。     

SGLT2抑制剂达格列净对2型糖尿病肾病患者血糖波动的影响

目的 探究SGLT2抑制剂达格列净对2型糖尿病肾病患者的血糖波动的影响。方法 选取2020年8月至2022年3月(含随访时间)中国科学技术大学附属第一医院(安徽省立医院)内分泌科收治的101例血糖控制不佳,且既往未使用钠葡萄糖协同转运蛋白2(SGLT2)抑制剂的2型糖尿病肾病住院患者,不含达格列净治疗作为对照组(n＝51),含达格列净治疗作为观察组(n＝50),比较两组患者治疗前后血糖波动及尿白蛋白肌酐比(UACR)的差异。结果 治疗1个月后,两组患者平均血糖(MBG)、血糖变异度(CV)、平均血糖标准差(SDBG)、平均血糖波动幅度(MAGE)、日间血糖平均绝对差(MODD)、高血糖(动态血糖值>10mmol/L)和低血糖(动态血糖值<3.1mmol/L)发生率均较治疗前下降,差异具有统计学意义(P<0.05),且观察组较对照组下降幅度大(P<0.05);两组患者治疗1、3、6个月后UACR也均较治疗前下降,差异具有统计学意义(P<0.05),观察组治疗后UACR较对照组下降幅度大(P<0.05)。结论 SGLT2抑制剂达格列净在控制2型糖尿病肾病患者的血糖方面更为稳定,且较少出现低血糖等不良反应,同时还可以有效降低UACR。     

射血分数轻度降低的心力衰竭患者应用钠-葡萄糖共转运蛋白2抑制剂的研究进展

钠-葡萄糖共转运蛋白2抑制剂即SGLT2抑制剂,最初是作为降糖药而开发的,现已被证明其可降低伴/不伴有动脉粥样硬化性心血管疾病（ASCVD）的2型糖尿病（T2DM）患者的心力衰竭住院（HFH）和心血管死亡风险。EMPEROR-Preserved实验研究评估了SGLT2抑制剂（恩格列净）对射血分数保留的心力衰竭（HFpEF）患者的临床疗效,结果表明,其临床效果可进一步扩大到射血分数轻度降低的心力衰竭（HFmrEF）患者中。虽然SGLT2抑制剂使降低心力衰竭发病率和预防心力衰竭恶化进入到新时代,但仍应继续寻找SGLT2抑制剂改善症状的关键机制,以保护患者免受心力衰竭致命进展的影响。本文就HFmrEF患者应用SGLT2抑制剂治疗进行综述,以期为HFmrEF患者的治疗提供理论指导。     

SGLT2 inhibitors: New medicines for addressing unmet needs in type 2 diabetes

The prevalence of type 2 diabetes mellitus (T2DM) is rising in Australia. Sodium glucose co-transporter 2 (SGLT2) inhibitors are an emerging treatment for T2DM. SGLT2 inhibitors offer a novel approach to lowering hyperglycaemia by suppressing renal glucose reabsorption and increasing urinary glucose excretion. The increased urinary glucose excretion has also been associated with caloric loss and osmotic diuresis. Dapagliflozin and canagliflozin are the SGLT2 inhibitors that are approved for clinical use in the US, the European Union (EU), and Australia. Their use results in reductions in HbA1c and body weight across a broad range of patient populations ranging from drug-naive patients to those who require additional therapy due to inadequate glycaemic control on their existing treatment. In addition, reductions in blood pressure (BP), particularly systolic BP, have also been noted. SGLT2 inhibitors are generally well tolerated with low rates of adverse events. Episodes of hypoglycaemia were mostly classified as minor, with low and balanced rates of severe hypoglycaemia across studies. The proportions of patients with genital infections and urinary tract infections were higher with dapagliflozin and canagliflozin versus their comparators. However, these infections were generally mild-to-moderate in intensity, treated with standard antimicrobial therapies, and rarely led to discontinuation. No dosage adjustments for dapagliflozin and canagliflozin are recommended for normal-to-mild renal impairment. Dapagliflozin and canagliflozin are not recommended for use in patients with eGFR<60 and <45mL/min/1.73m², respectively. Overall, SGLT2 inhibitors have shown the potential to become an important addition to the treatment armamentarium for effective management of patients with T2DM.     

严重急性呼吸综合征冠状病毒2主要蛋白质分子的氨基酸变异分析

目的 应用生物物理学方法鉴定分析严重急性呼吸综合征冠状病毒2（SARS-CoV-2）中主要蛋白质分子的关键氨基酸变异。方法 通过氨基酸序列同源比对、突变氨基酸残基分类、蛋白质三维结构重建和氨基酸残基静电相互作用测量,以同源性最高的蝙蝠冠状病毒RaTG13为参照,进行SARS-CoV-2中主要蛋白质分子的关键氨基酸变异分析。结果 初步分析确定SARS-CoV-2中RNA依赖的RNA聚合酶（RdRp）、核糖核酸外切酶（ExoN）、尿苷酸特异性核糖核酸内切酶（NendoU）和刺突蛋白（S蛋白）上至少发生了10处影响静电相互作用的氨基酸变异,这些变异可能影响蛋白质分子的空间构象及其生物学功能。结论 初步确定了SARS-CoV-2中主要蛋白质分子的关键氨基酸变异,为理解SARS-CoV-2的遗传特性、致病性和流行病学特征提供了有用线索。