Abstract
The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported. The synthetic methodology provides access to diverse monomer building blocks amenable to solid-phase assembly in just four synthetic steps. The conformational flexibility of model dimers was investigated using a combination of solid and solution state methodologies supplemented with DFT calculations. The lack of noncovalent constraints allows for significant conformational plasticity in the scaffold, thus permitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.
Highlights
The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported
The most common molecular recognition scaffold in multiprotein complexes is the α-helix, and as such, numerous strategies to target this class of PPI using rationally designed molecules have been reported, including both peptidic and nonpeptidic approaches, a concept known as peptidomimetics.[6,7]
Helix mimetics possess two common features: a rigid scaffold to mimic the rod-like morphology of the helical backbone and side chains to recapitulate the spatial orientation of hotspot residues on the native helix.[8]
Summary
The authors thank Dr Lisa Haigh, Imperial College London for mass spectrometry and Prof. A.B. and C.R. thank Imperial College London for their Junior Research Fellowships.
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