Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 West Beichen Rd. No. 5, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Biotechnol Lett. 2022 Oct;44(10):1149-1162. doi: 10.1007/s10529-022-03288-1. Epub 2022 Aug 25.
We constructed a recombinant oral GLP-1 analogue in Lactococcus lactis (L. lactis) and evaluated its physiological functions.
In silico docking suggested the alanine at position 8 substituted with serine (A8SGLP-1) reduced binding of DPP4, which translated to reduced cleavage by DPP4 with minimal changes in stability. This was further confirmed by an in vitro enzymatic assay which showed that A8SGLP-1 significantly increased half-life upon DPP4 treatment. In addition, recombinant L. lactis (LL-A8SGLP-1) demonstrated reduced fat mass with no changes in body weight, significant improvement of random glycemic control and reduced systemic inflammation compared with WT GLP-1 in db/db mice.
LL-A8SGLP-1 adopted in live biotherapeutic products reduce blood glucose in db/db mice without affecting its function.
我们构建了乳酸乳球菌（L. lactis）中的重组口服 GLP-1 类似物，并评估了其生理功能。
计算机对接表明，第 8 位的丙氨酸被丝氨酸取代（A8SGLP-1）可降低 DPP4 的结合，这意味着 DPP4 的切割减少，而稳定性的变化最小。体外酶测定进一步证实，A8SGLP-1 经 DPP4 处理后半衰期显著延长。此外，与野生型 GLP-1 相比，重组乳酸乳球菌（LL-A8SGLP-1）在 db/db 小鼠中表现出脂肪量减少，体重无变化，随机血糖控制显著改善，全身炎症减少。
活生物治疗产品中采用的 LL-A8SGLP-1 可降低 db/db 小鼠的血糖，而不影响其功能。
