Abstract
A four‐membered oxygen ring (oxetane) can be readily grafted into native peptides and proteins through site‐selective bis‐alkylation of cysteine residues present as disulfides under mild and biocompatible conditions. The selective installation of the oxetane graft enhances stability and activity, as demonstrated for a range of biologically relevant cyclic peptides, including somatostatin, proteins, and antibodies, such as a Fab arm of the antibody Herceptin and a designed antibody DesAb‐Aβ against the human Amyloid‐β peptide. Oxetane grafting of the genetically detoxified diphtheria toxin CRM197 improves significantly the immunogenicity of this protein in mice, which illustrates the general utility of this strategy to modulate the stability and biological activity of therapeutic proteins containing disulfides in their structures.
Highlights
A four-membered oxygen ring can be readily grafted into native peptides and proteins through siteselective bis-alkylation of cysteine residues present as disulfides under mild and biocompatible conditions
We extended our stapling strategy to the antibody DesAb-Ab3-9, which was designed to target the region 3–9 of human Amyloid-b (Ab42) peptide, the aggregation of which is a hallmark of Alzheimers disease.[21]
To demonstrate the practical application of our method to therapeutic proteins, we investigated the effects of the selective introduction of the oxetane staple into the genetically detoxified diphtheria toxin CRM197, which features four Cys residues in the form of two disulfides
Summary
A four-membered oxygen ring (oxetane) can be readily grafted into native peptides and proteins through siteselective bis-alkylation of cysteine residues present as disulfides under mild and biocompatible conditions.
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