Insulin analogs for the treatment of diabetes mellitus: therapeutic applications of protein engineering.
Insulin analogs for the treatment of diabetes mellitus: therapeutic applications of protein engineering.
复制标题
DOI：
10.1111/j.1749-6632.2012.06468.x
复制
发表时间：
2011-12
影响因子：
5.2
通讯作者：
Weiss MA
中科院分区：
文献类型：
--
作者：
Berenson DF;Weiss AR;Wan ZL;Weiss MA
胰岛素类似物的工程设计代表了基于结构的蛋白质设计的胜利。胰岛素六聚体的结构提供了一个框架。含有二聚体的锌配位三聚体，这种结构代表了活性胰岛素单体的储存形式。最初的研究集中在亚基界面的不稳定上。因为分解促进了毛细血管吸收，这种靶向不稳定使速效胰岛素类似物得以发展。为了稳定胰岛素六聚体，促进皮下储库内的高阶自组装，以达到加强基础血糖控制和降低低血糖风险的目标，研究人员进行了相反的努力。目前的产品要么通过等电沉淀（甘精胰岛素，Lantus®的活性成分，赛诺菲-安万特），要么采用白蛋白结合的酰基链（胰岛素，Levemir®的活性成分，诺和诺德）。为了进一步改善药代动力学性质，目前正在研究改进的方法。最近提出了基于皮下超分子组装的新策略(a)胰岛素六聚体的大规模变构重组（TR转变），(b)锌离子与六聚体表面工程His-X3-His位点的ph依赖性结合，或(c)葡萄糖响应聚合物调节激素释放的长期愿景。这种设计与野生型胰岛素和目前的胰岛素产品一样，在室温以上易降解，因此它们的输送、储存和使用需要富裕社会的基础设施。考虑到治疗供应链的全球维度，我们设想超稳定蛋白质模拟物配方的并行工程将使发展中国家的贫困患者受益。
The engineering of insulin analogs represents a triumph of structure-based protein design. A framework has been provided by structures of insulin hexamers. Containing a zinc-coordinated trimer of dimers, such structures represent a storage form of the active insulin monomer. Initial studies focused on destabilization of subunit interfaces. Because disassembly facilitates capillary absorption, such targeted destabilization enabled development of rapid-acting insulin analogs. Converse efforts were undertaken to stabilize the insulin hexamer and promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus®; Sanofi-Aventis) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir®; Novo-Nordisk). To further improve pharmacokinetic properties, modified approaches are presently under investigation. Novel strategies have recently been proposed based on subcutaneous supramolecular assembly coupled to (a) large-scale allosteric reorganization of the insulin hexamer (the TR transition), (b) pH-dependent binding of zinc ions to engineered His-X3-His sites at hexamer surfaces, or (c) the long-range vision of glucose-responsive polymers for regulated hormone release. Such designs share with wild-type insulin and current insulin products a susceptibility to degradation above room temperature, and so their delivery, storage, and use require the infrastructure of an affluent society. Given the global dimensions of the therapeutic supply chain, we envisage that concurrent engineering of ultra-stable protein analog formulations would benefit underprivileged patients in the developing world.
登录
查看更多内容
影响因子：
17.1
作者：
Brown L;Edelman ER
通讯作者：
Edelman ER
影响因子：
3.8
作者：
Baxter, Mike A.
通讯作者：
Baxter, Mike A.
DOI：
10.1098/rstb.1988.0058
发表时间：
1988-07-06
影响因子：
6.3
作者：
BAKER, EN;BLUNDELL, TL;VIJAYAN, NM
通讯作者：
VIJAYAN, NM
影响因子：
8.2
作者：
Brange, J
通讯作者：
Brange, J
影响因子：
8.2
作者：
Blin, P.;Lassalle, R.;Dureau-Pournin, C.;Ambrosino, B.;Bernard, M. A.;Abouelfath, A.;Gin, H.;Le Jeunne, C.;Pariente, A.;Droz, C.;Moore, N.
通讯作者：
Moore, N.