Researchers in Hong Kong and Germany have presented a new chemical ligation strategy to design peptides with a range of complex structural features. The group, led by Xuechen Li at the University of Hong Kong, used benzofuran groups to incorporate salicylaldehyde esters into the peptide side chains, allowing them to build a variety of peptide scaffolds. The group hopes that their work will open new avenues for synthetic peptides and inspire the design of new protein-protein interaction inhibitors, a critical class of therapeutics for numerous diseases.
Pharmaceuticals are often small molecules that target enzymes and receptors and bind selectively in the deep pockets of their substrate to achieve the desired effect. However, many biological processes instead depend on interactions between large, flat and flat protein surfaces. Research has shown that abnormalities in protein-protein interactions (PPI) can be pathogenic, prompting chemists to develop molecules that can interfere with PPIs. This poses a challenge for synthetic chemists because typical small molecule inhibitors are often less effective in interacting with the relatively imperceptible protein surfaces involved in PPIs. Synthetic peptides are a promising alternative because their larger size and tunable conformational features enable effective binding to protein surfaces. Unfortunately, peptides have their own limitations, including their susceptibility to protease degradation and limited cell membrane permeability. Recent research efforts have focused on overcoming these problems through careful structural modifications.
The Li group develops ligation strategies to link peptide segments via their side chains in order to construct highly specific peptide architectures. However, installing reactive salicylaldehyde ester groups on peptide side chains has proven to be an ongoing challenge as many are not stable to the resin cleavage step in solid phase peptide synthesis. Now Li’s group has overcome these limitations by masking the salicylaldehyde ester as a benzofuran unit, which upon ozonolysis releases the salicylaldehyde ester for subsequent chemoselective ligation. To demonstrate the scope and usefulness of their strategy, the group demonstrated that various classes of peptides were accessible through their synthetic route, including branched, bridged, tail-shaped cyclic, and multicyclic peptides.
“The beauty of chemoselective ligation reactions is their ability to form covalent bonds in complex environments, often without the addition of reagents or catalysts,” comments Jeffrey Bode, an expert in synthetic organic chemistry and organic protein synthesis at the Swiss Federal Institute of Technology, ETH Zurich. However, the burned-in reactivity of the ligation handles often makes it difficult to incorporate the most important functional groups into peptides and proteins, since such groups are often not stable against resin cleavage or protein folding. [The group’s] An elegant strategy enables the construction of a number of topologically unique cyclic peptides. ‘
Li hopes the group can expand its strategy further. ‘We want to develop peptide ligation methods that enable cyclic peptide synthesis of higher order … [as] There are still many possible peptide architectures that remain to be explored. We hope to apply this chemistry to real-world development of peptide-PPI inhibitors and peptide-drug conjugates. ‘