Zinc(II)cyclen–peptide conjugates interacting with the weak effector binding state of Ras

Abstract

Zinc(II)cyclen–peptide hybrid compounds and bis-zinc(II)cyclen complexes are prepared as potential
binders of the guanine nucleotide binding protein Ras, an important molecular switch in cellular signal
transduction. The design of the compounds is based on the previous observation that zinc(II)cyclen complexes
could serve as lead compounds for inhibitors of Ras-effector interaction and thus be able to interrupt
Ras induced signal transduction. Zinc(II)cyclen selectively stabilizes conformational state 1 of active
Ras, a conformational state with drastically decreased affinity to effector proteins like Raf-kinase. To
achieve higher binding affinities of such Ras–Raf interaction inhibitors, zinc(II)cyclen conjugates with
short peptides, derived from the sequence of the Ras-activator SOS, were prepared by solid phase synthesis
protocols. Dinuclear bis-zinc(II)cyclen complexes were obtained from alkyne-azide cycloaddition
reactions. NMR investigations of the prepared compounds revealed that the peptide conjugates do not
lead to an increase in Ras binding affinity of the metal complex–peptide conjugates. The dinuclear zinc
complexes lead to an immediate precipitation of the protein prohibiting spectroscopic investigations
of their binding.