当前位置: X-MOL 学术J. Biol. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The discovery and maturation of peptide biologics targeting the small G-protein Cdc42: A bioblockade for Ras-driven signaling.
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2020-01-20 , DOI: 10.1074/jbc.ra119.010077
George J N Tetley 1 , Natasha P Murphy 1 , Stephane Bonetto 2 , Gabriela Ivanova-Berndt 2 , Jefferson Revell 3 , Helen R Mott 1 , R Neil Cooley 2 , Darerca Owen 1
Affiliation  

Aberrant Ras signaling drives 30% of cancers, and inhibition of the Rho family small GTPase signaling has been shown to combat Ras-driven cancers. Here, we present the discovery of a 16-mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely-related small GTPases. The structure of the tightest binding peptide was solved by NMR, and its binding site on Cdc42 was determined. Addition of a cell-penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signaling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such, they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data add to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.

中文翻译:

针对小G蛋白Cdc42的肽生物制剂的发现和成熟:Ras驱动信号的生物封锁。

异常的Ras信号传导可驱动30%的癌症,而Rho家族小GTPase信号传导的抑制作用已显示可抵抗Ras引起的癌症。在这里,我们提出了发现一个16-mer环状肽的发现,该肽以纳摩尔亲和力与Cdc42结合。该序列的亲和力成熟产生了一组衍生的候选物,其对其他紧密相关的小GTP酶具有增加的亲和力和调节的特异性。通过NMR解析最紧密结合肽的结构,并确定其在Cdc42上的结合位点。细胞穿透序列的添加使肽能够进入细胞内部并与它们的靶标结合,从而调节信号传导途径。在Ras驱动的癌细胞模型中,这些肽对增殖具有抑制作用,并显示出对侵袭和运动的抑制作用。因此,它们代表了Rho系列小型GTPase抑制剂和靶向Ras致癌的疗法的有希望的候选者。我们的数据增加了越来越多的文献,证明了肽在药物发现的生物学领域中正在确立自己的地位。
更新日期:2020-02-28
down
wechat
bug