Water-soluble β-strand peptidomimetics designed for diverse sequences and aqueous target binding

Targeting protein-protein interactions (PPIs) is a highly promising therapeutic strategy for a myriad of diseases, yet it presents significant challenges. Traditional small molecules often struggle to engage the large, flat surfaces characteristic of PPI interfaces, while natural peptides suffer from poor stability and bioavailability. The development of non-peptidic scaffolds that mimic key secondary structural elements, like β-strands, offers a compelling solution by combining the binding specificity of peptides with the drug-like properties of small molecules, addressing a critical gap in drug discovery.

Researchers developed an improved synthetic route for β-strand peptidomimetics, building upon previous proof-of-principle syntheses. The core scaffold consists of alternating (hetero)aromatic and cyclic urea units. The primary goal was to demonstrate sequence diversity by incorporating both hydrophobic and hydrophilic side-chain mimics. The team focused on ensuring the scaffold's conformational preorganization for target binding in aqueous media, including buffer, and confirming its ready solubility. This involved careful design and synthesis to achieve the desired structural and solubility properties for future deployment against specific protein targets.

The improved synthetic route successfully enabled the incorporation of diverse side-chain mimics, expanding the sequence diversity of the β-strand peptidomimetics. Crucially, the designed scaffold maintains its conformational preorganization, which is essential for effective target binding, even in aqueous media such as buffer. This preorganization was previously confirmed to be in good agreement with the i, i + 2, and i + 4 side-chain vectors of a canonical β-strand, driven by dipolar repulsion in organic solvents. The new mimetics also exhibited ready solubility, a critical property for biological applications. This combination of sequence diversity, conformational stability in aqueous environments, and high solubility makes these peptidomimetics highly suitable for further elaboration and application.

The developed β-strand peptidomimetics are conformationally preorganised for target binding in aqueous media and are readily soluble, enabling their deployment against specific protein targets.