Department of Nephrology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 53300, Guangxi, PR China.
Center for Systemic Inflammation Research, School of Preclinical Medicine, Youjiang Medical University for Nationalities, Baise 53300, Guangxi, PR China.
Life Sci. 2021 Apr 1;270:119136. doi: 10.1016/j.lfs.2021.119136. Epub 2021 Jan 27.
To prolong the short lifespan of oxyntomodulin (OXM) for treating obesity and diabetes, we designed a novel fused OXM analog, containing an albumin-binding sequence, a protease cleavable tetrapeptide, and a mutated OXM.
We screened two albumin-binding sequences (S3 and S6) to construct OXM derivatives, termed S3-2 (with two cysteines) and S6-0 (without cysteine). After peptides were synthesized, isothermal titration calorimetry (ITC) was applied to assess binding-affinity for HSA. Further in vivo acute efficacies evaluation and candidate selection were performed in diabetic db/db mice via oral glucose tolerance test (OGTT) and glucose-lowering duration test. Chronic efficacy test of selected candidate was also performed in diabetic mice.
Firstly, S3-2 and S6-0 with purity over 99% were prepared. ITC measurements demonstrated that S3-2 and S6-0 associate with HSA with high-affinity (K = 12.81 ± 1.11 nM and 26.98 ± 2.39 nM, respectively). Then hypoglycemic efficacies showed deoxidation S3-2 (S3-2re) showed longer hypoglycemic duration than the oxidation one (S3-2ox), and better blood glucose level (BGL) control effect than S6-0. OGTTs in diabetic mice revealed the glucose-lowering efficacies of S3-2re were similar to Liraglutide. The protracted antidiabetic effects of S3-2re were further confirmed by multiple OGTTs in db/db mice. Furthermore, twice weekly injection of S3-2re to db/db mice achieved beneficial effects on body weight gain, glucose tolerance, postprandial BGL and obesity. Moreover, S3-2 produces significantly protective effects on the impaired renal functions of the diabetic mice.
S3-2re exhibits outstanding therapeutical potential as a candidate drug for treating the obesity and diabetes.
为了延长氧结合素（OXM）的半衰期以用于肥胖症和糖尿病的治疗，我们设计了一种新型融合型 OXM 类似物，其中包含白蛋白结合序列、可被蛋白酶切割的四肽和突变型 OXM。
我们筛选了两个白蛋白结合序列（S3 和 S6）来构建 OXM 衍生物，分别命名为 S3-2（含两个半胱氨酸）和 S6-0（不含半胱氨酸）。肽合成后，采用等温滴定量热法（ITC）评估与 HSA 的结合亲和力。进一步通过口服葡萄糖耐量试验（OGTT）和降血糖持续时间试验在糖尿病 db/db 小鼠中进行了急性药效评价和候选药物筛选，然后在糖尿病小鼠中进行了候选药物的慢性药效试验。
首先，制备了纯度超过 99%的 S3-2 和 S6-0。ITC 测量表明，S3-2 和 S6-0 与 HSA 具有高亲和力（分别为 K=12.81±1.11 nM 和 26.98±2.39 nM）。随后的降血糖效果表明，还原型 S3-2（S3-2re）的降血糖持续时间长于氧化型 S3-2（S3-2ox），且对血糖水平（BGL）的控制效果优于 S6-0。糖尿病小鼠的 OGTT 结果表明，S3-2re 的降血糖效果与利拉鲁肽相似。S3-2re 在 db/db 小鼠中的多次 OGTT 进一步证实了其抗糖尿病作用的持久性。此外，每周两次给 db/db 小鼠注射 S3-2re 可有效抑制体重增加、改善葡萄糖耐量、降低餐后 BGL 和肥胖。此外，S3-2 对糖尿病小鼠受损的肾功能具有显著的保护作用。
S3-2re 作为治疗肥胖症和糖尿病的候选药物具有突出的治疗潜力。
