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

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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.