Dynamic helices that undergo exchange between P and M conformations can be used as sensors when their interactions with chiral substances results in a helix handedness bias. For instance, chiral induction in short helically folded aromatic oligoamides based on 8‐amino‐2‐quinoline carboxylic acid (Q) has been used to detect interactions with proteins and nucleic acids. However, the stability of these helices in water increases rapidly with oligomer length to the extent that helix dynamics become too slow for sensing applications. We have developed an approach to enhance the helix dynamics of these oligomers through the introduction of more flexible 6‐aminomethyl‐2‐pyridinecarboxylic acid units (P) while preserving helix integrity. A series of P/Q hybrid oligoamides were synthesized and their rate of helix handedness inversion was evaluated by monitoring induced circular dichroism so as to define the requirements to bring kinetics in a practical range for sequences as long as fourteen units. Proof of principle was then brought by confining such sequences at the surface of carbonic anhydrase and showing that protein‐mediated helix handedness induction occurs.
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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