Heterogeneous-Backbone Proteomimetic Analogues of Lasiocepsin, a Disulfide-Rich Antimicrobial Peptide with a Compact Tertiary Fold.
Heterogeneous-Backbone Proteomimetic Analogues of Lasiocepsin, a Disulfide-Rich Antimicrobial Peptide with a Compact Tertiary Fold.
复制标题
DOI：
10.1021/acschembio.2c00138
复制
发表时间：
2022-04-15
影响因子：
4
通讯作者：
Horne, W. Seth
中科院分区：
文献类型：
--
作者：
Cabalteja, Chino C.;Lin, Qiao;Harmon, Thomas W.;Rao, Shilpa R.;Di, Y. Peter;Horne, W. Seth
细菌对临床使用的抗生素产生耐药性是公共卫生中的一个重大问题。天然抗菌肽（AMPs）是抗生素的宝贵来源，其作用机制不易产生耐药性。为了实现amp的前景，同时克服诸如生物稳定性差等限制，研究人员已经寻找具有人工酰胺基骨架的序列定义低聚物，这些低聚物显示出与天然药物相似的膜破坏功能。这一先例大多集中在短肽模拟类似物的非结构化链或次级折叠；然而，天然抗菌武器库包括一些通过有序三级结构起作用的中小型蛋白质。由于模仿目标的复杂性增加，产生这些支架的蛋白质模拟类似物提出了挑战。在这里，我们报道了lasiocepsin异质性主干变异的发展，lasiocepsin是一种在蜂毒中发现的富含27个残基二硫化物的AMP，采用紧凑的三级折叠。设计、合成和生物学评价的迭代循环产生了天然结构域的类似物，其人工骨架含量约为30-40%，具有相当的抗菌活性，降低了宿主细胞毒性，并且提高了蛋白水解降解的稳定性。通过核磁共振确定的几种变体的高分辨率结构提供了对骨干组成，第三纪褶皱和生物特性之间相互作用的见解。总之，本文报道的结果扩大了通过三级折叠模式的人工骨干类似物来模拟蛋白质功能的范围，并表明蛋白质骨干工程可以通过对蛋白质折叠结构施加位点特异性控制来调节蛋白质功能。
The emergence of resistance to clinically used antibiotics by bacteria presents a significant problem in public health. Natural antimicrobial peptides (AMPs) are a valuable source of antibiotics that act by a mechanism less prone to the evolutionary development of resistance. In an effort to realize the promise of AMPs while overcoming limitations such as poor biostability, researchers have sought sequence-defined oligomers with artificial amide-based backbones that show similar membrane disrupting functions to natural agents. Most of this precedent has focused on short peptidomimetic analogues of unstructured chains or secondary folds; however, the natural antimicrobial arsenal includes a number of small and medium sized proteins that act via an ordered tertiary structure. Generating proteomimetic analogues of these scaffolds poses a challenge due to the increased complexity of the target for mimicry. Here, we report the development of heterogeneous-backbone variants of lasiocepsin, a 27-residue disulfide-rich AMP found in bee venom that adopts a compact tertiary fold. Iterative cycles of design, synthesis, and biological evaluation yielded analogues of the natural domain with ~30–40% artificial backbone content, comparable antibacterial activity, reduced host cell toxicity, and improved stability to proteolytic degradation. High-resolution structures determined for several variants by NMR provide insights into the interplay among backbone composition, tertiary fold, and biological properties. Collectively, the results reported here broaden the scope of protein functional mimicry by artificial backbone analogues of tertiary folding patterns and suggest protein backbone engineering as a means to tune protein function by exerting site-specific control over protein folded structure.
登录
查看更多内容
影响因子：
15
作者：
Haase, Holly S.;Peterson-Kaufman, Kimberly J.;Levengood, Sheeny K. Lan;Checco, James W.;Murphy, William L.;Gellman, Samuel H.
通讯作者：
Gellman, Samuel H.
影响因子：
2.2
作者：
KIM, YM;PRESTEGARD, JH
通讯作者：
PRESTEGARD, JH
影响因子：
13.8
作者：
Izadpanah, A;Gallo, RL
通讯作者：
Gallo, RL
影响因子：
15
作者：
George KL;Horne WS
通讯作者：
Horne WS
影响因子：
6.8
作者：
Bradshaw, JP
通讯作者：
Bradshaw, JP