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An Albumin Sandwich Enhances in Vivo Circulation and Stability of Metabolically Labile Peptides.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-06-06 , DOI: 10.1021/acs.bioconjchem.9b00258 Rui Tian 1 , Shoujun Zhu , Qiao Zeng , Lixin Lang , Ying Ma , Dale O Kiesewetter , Yi Liu , Xiao Fu , Joseph Lau , Guizhi Zhu , Orit Jacobson , Zhantong Wang , Yunlu Dai , Guocan Yu , Bernard R Brooks , Gang Liu 1 , Gang Niu , Xiaoyuan Chen
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-06-06 , DOI: 10.1021/acs.bioconjchem.9b00258 Rui Tian 1 , Shoujun Zhu , Qiao Zeng , Lixin Lang , Ying Ma , Dale O Kiesewetter , Yi Liu , Xiao Fu , Joseph Lau , Guizhi Zhu , Orit Jacobson , Zhantong Wang , Yunlu Dai , Guocan Yu , Bernard R Brooks , Gang Liu 1 , Gang Niu , Xiaoyuan Chen
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The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.
中文翻译：
白蛋白三明治增强体内循环和代谢不稳定肽的稳定性。
不良的药代动力学阻碍了许多分子药物的有效性。与以前效果有限的方法不同，最近，用于内源性白蛋白体内搭便的新兴高亲和力白蛋白结合部分（ABM）为伴侣分子小分子开辟了一条长途治疗之路。尽管几种FDA批准的脂肪酸已显示出延长的驻留时间和治疗效果，但迫切需要一种易于合成，水溶性且具有多种载药量的高效ABM，以提高短命构建体的治疗效果。通过计算模型筛选和有效的合成方案，我们在本文中确定了一种理想的二价伊文思蓝衍生物，称为N（tEB）2，作为伴侣短命分子的智能ABM传递平台。最佳的N（tEB）2可以通过两个带有一个优选间隔基的结合头可逆地连接两个白蛋白分子，从而显着延长了预载货物和水溶性货物的循环半衰期。值得注意的是，这种白蛋白的原位二聚化能够将肽治疗剂夹在中间，以保护它们免受蛋白水解作用。作为应用，我们将N（tEB）2与exendin-4偶联用于糖尿病小鼠模型中的长效葡萄糖控制，它优于先前测试的NtEB-exendin-4（Abextide）和新的FDA批准的semaglutide ，可以说是迄今为止最好的商业每周公式。因此，这种新型白蛋白结合剂对于下一代仿生药物递送系统具有极好的临床潜力。
更新日期：2019-05-13
中文翻译：
白蛋白三明治增强体内循环和代谢不稳定肽的稳定性。
不良的药代动力学阻碍了许多分子药物的有效性。与以前效果有限的方法不同，最近，用于内源性白蛋白体内搭便的新兴高亲和力白蛋白结合部分（ABM）为伴侣分子小分子开辟了一条长途治疗之路。尽管几种FDA批准的脂肪酸已显示出延长的驻留时间和治疗效果，但迫切需要一种易于合成，水溶性且具有多种载药量的高效ABM，以提高短命构建体的治疗效果。通过计算模型筛选和有效的合成方案，我们在本文中确定了一种理想的二价伊文思蓝衍生物，称为N（tEB）2，作为伴侣短命分子的智能ABM传递平台。最佳的N（tEB）2可以通过两个带有一个优选间隔基的结合头可逆地连接两个白蛋白分子，从而显着延长了预载货物和水溶性货物的循环半衰期。值得注意的是，这种白蛋白的原位二聚化能够将肽治疗剂夹在中间，以保护它们免受蛋白水解作用。作为应用，我们将N（tEB）2与exendin-4偶联用于糖尿病小鼠模型中的长效葡萄糖控制，它优于先前测试的NtEB-exendin-4（Abextide）和新的FDA批准的semaglutide ，可以说是迄今为止最好的商业每周公式。因此，这种新型白蛋白结合剂对于下一代仿生药物递送系统具有极好的临床潜力。
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