抗KRAS環状ペプチドファマコフォアの小型タンパク質へのラソグラフト体の創出

两个抗KRAS的多肽(Kd2和KWT9)已经被嫁接到泛素上，以提供具有不同选择性的两代杂交结构。KD2派生的Ubody对于KRAS的“开”和“关”状态是有选择性的。KWT9是新发现的，与健康蛋白相比，它对突变的KRAS表现出(及其UBody衍生物)选择性。新一代的无人机也被开发出来了。初步评估显示，几种命中化合物对恶性靶蛋白具有良好的活性，并且比健康蛋白和/或“关”状态有更好的选择性。合作者的早期结果证实了多肽的潜力，尽管还需要对UBody进行进一步的实验工作。UBody开发的整个工作流程现在已经简化，从肽点击鉴定、套索移植系绳优化、表达和纯化到结合动力学估计。这一实验方案现在可以应用于不同的目标。该项目剩下的主要挑战是通过病毒载体转染法将UBody运送到细胞内。

Two anti-KRas peptides (KD2 and KWT9) have been grafted to Ubiquitin to provide two initial generations of hybrid constructs called “Ubodies” with different selectivity profiles. KD2-derived Ubodies are selective for the KRas “on” vs “off” state. KWT9 is newly identified, and displays (together with its Ubody derivatives) selectivity towards the mutant KRas over the healthy protein. A further generation of de novo Ubodies was also developed. Initial evaluation shows several hit compounds featuring excellent activity on the malignant target protein and selectivity over the healthy protein and/or the “off” state. Early results from collaborators validate the potential of the peptides, although further experimental work is needed on the Ubodies. The overall workflow for Ubody development has now been streamlined, from peptide hit identification, lasso-graft tether optimization, expression and purification to binding kinetics estimation. This experimental scheme can now be applied to different targets. The main challenge remaining to this project is now the delivery of the Ubodies into the cell by viral vector transfection.