In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right-handed and left-handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer-protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 Å resolution and revealed a number of unanticipated protein-foldamer, foldamer-foldamer, and protein-protein interactions.
Helically
folded aromatic foldamers may constitute suitable candidates for the ab initio design of ligands for protein surfaces. As preliminary
steps toward the exploration of this hypothesis, a tethering approach
was developed to detect interactions between a protein and a foldamer
by confining the former at the surface of the latter. Cysteine mutants
of two therapeutically relevant enzymes, CypA and IL4, were produced.
Two series of ten foldamers were synthesized bearing different proteinogenic
side chains and either a long or a short linker functionalized with
an activated disulfide. Disulfide exchange between the mutated cysteines
and the activated disulfides yielded 20 foldamer-IL4 and 20 foldamer-CypA
adducts. Effectiveness of the reaction was demonstrated by LC-MS,
by MS analysis after proteolytic digestion, and by 2D NMR. Circular
dichroism then revealed diastereoselective interactions between the
proteins and the foldamers confined at their surface which resulted
in a preferred handedness of the foldamer helix. Helix sense bias
occurred sometimes with both the short and the long linkers and sometimes
with only one of them. In a few cases, helix handedness preference
is found to be close to quantitative. These cases constitute valid
candidates for structural elucidation of the interactions involved.
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