Biomimicry of surfactant protein C.
Biomimicry of surfactant protein C.
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DOI：
10.1021/ar800058t
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发表时间：
2008-10
影响因子：
18.3
通讯作者：
Barron, Annelise E.
中科院分区：
文献类型：
--
作者：
Brown, Nathan J.;Johansson, Jan;Barron, Annelise E.
由于外源性肺表面活性物质广泛用于治疗新生儿呼吸窘迫综合征，早产儿存活率和呼吸系统发病率显著提高。尽管动物源性表面活性剂制剂具有一定的有效性，但在使用过程中仍存在一些问题和困难。这促使了对合成表面活性剂制剂的研究。然而，迄今为止，没有临床使用的合成制剂是有效的天然材料。这主要是因为以前的合成配方缺乏肺表面活性剂系统疏水蛋白的类似物，SP-B和SP-C，这是关键的功能成分。因此，最近的研究转向了新一代合成的仿生表面活性剂的开发，这些表面活性剂含有合成磷脂以及肺表面活性剂疏水蛋白部分的模拟物。在这篇文章中，我们详细介绍了我们在制造用于合成表面活性剂替代疗法的SP-C精确模拟物方面所做的努力。尽管SP-C的结构看似简单，但考虑到其极端的疏水性和结构不稳定性，这种以螺旋为主的蛋白质非常具有挑战性，这极大地复杂化了有效SP-C类似物的创建。从自然中获得灵感，两种有前途的仿生方法导致了合理设计的生物聚合物的创造，这些聚合物再现了许多SP-C的分子特征。第一种方法利用详细的SP-C结构-活性关系和氨基酸折叠倾向来创建基于肽的类似物SP-C33。在SP-C33中，有问题的和亚稳的聚缬氨酸螺旋被结构稳定的聚亮氨酸螺旋取代，并包含一个位置良好的正电荷以防止聚集。SP-C33不仅结构稳定，而且消除了天然蛋白的结合倾向。第二种方法遵循相同的设计考虑，但使用非天然的聚n-取代甘氨酸或“肽类”支架来规避与SP-C相关的困难。通过在非天然骨架中加入独特的仿生侧链，类肽模拟物捕获了SP-C的疏水模式和螺旋二级结构。尽管在结构上存在差异，SP-C33和SP-C肽样模拟物都具有SP-C的许多必要特征。在表面活性剂环境中，这些类似物还可以复制功能性仿生表面活性剂治疗所需的许多关键表面活性，同时克服与天然蛋白质相关的困难。这些仿生表面活性剂配方具有更好的稳定性、更大的生产潜力和消除可能的致病性污染的潜力，不仅可以改善呼吸窘迫综合征的治疗，而且还可以治疗其他呼吸相关疾病。
Since the widespread use of exogenous lung surfactant to treat neonatal respiratory distress syndrome, premature infant survival and respiratory morbidity have dramatically improved. Despite the effectiveness of the animal-derived surfactant preparations, there still remain some concerns and difficulties associated with their use. This has prompted investigation into the creation of synthetic surfactant preparations. However, to date, no clinically used synthetic formulation is as effective as the natural material. This is largely because the previous synthetic formulations lacked analogues of the hydrophobic proteins of the lung surfactant system, SP-B and SP-C, which are critical functional constituents. As a result, recent investigation has turned towards the development of a new generation of synthetic, biomimetic surfactants that contain synthetic phospholipids along with a mimic of the hydrophobic protein portion of lung surfactant. In this Account, we detail our efforts in creating accurate mimics of SP-C for use in a synthetic surfactant replacement therapy. Despite SP-C’s seemingly simple structure, the predominantly helical protein is extraordinarily challenging to work with given its extreme hydrophobicity and structural instability, which greatly complicates the creation of an effective SP-C analogue. Drawing inspiration from Nature, two promising biomimetic approaches have led to the creation of rationally designed biopolymers that recapitulate many of SP-C’s molecular features. The first approach utilizes detailed SP-C structure-activity relationships and amino acid folding propensities to create a peptide-based analogue, SP-C33. In SP-C33, the problematic and metastable poly-valine helix is replaced with a structurally stable, poly-leucine helix and includes a well placed positive charge to prevent aggregation. SP-C33 is both structurally stable and eliminates the association propensity of the native protein. The second approach follows the same design considerations, but makes use of a non-natural, poly-N-substituted glycine or “peptoid” scaffold to circumvent the difficulties associated with SP-C. By incorporating unique, biomimetic side chains in a non-natural backbone, the peptoid mimic captures both SP-C’s hydrophobic patterning and helical secondary structure. Despite the differences in structure, both SP-C33 and the SP-C peptoid mimic capture many requisite features of SP-C. In a surfactant environment, these analogues also replicate many of the key surface activities necessary for a functional biomimetic surfactant therapy while overcoming the difficulties associated with the natural protein. With improved stability, greater production potential, and elimination of possible pathogenic contamination, these biomimetic surfactant formulations offer the potential not only to improve the treatment of respiratory distress syndrome, but also the opportunity to treat other respiratory-related disorders.
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DOI：
10.1164/ajrccm.154.2.8756826
发表时间：
1996-08-01
影响因子：
24.7
作者：
Hawgood, S;Ogawa, A;Benson, B
通讯作者：
Benson, B
影响因子：
3.4
作者：
Gericke, A;Flach, CR;Mendelsohn, R
通讯作者：
Mendelsohn, R
影响因子：
3.4
作者：
Alonso, C;Waring, A;Zasadzinski, JA
通讯作者：
Zasadzinski, JA
影响因子：
2.9
作者：
JOHANSSON, J;SZYPERSKI, T;WUTHRICH, K
通讯作者：
WUTHRICH, K
影响因子：
2.9
作者：
Bi, XH;Flach, CR;Mendelsohn, R
通讯作者：
Mendelsohn, R