An Efficient, Site-Selective and Spontaneous Peptide Macrocyclisation During in vitro Translation

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Organic Chemistry

Background:

• Peptide macrocyclisation enhances peptide properties like stability and cell permeability.
• Existing methods face limitations in efficiency and applicability.

Purpose of the Study:

• To introduce a new cyanobenzothiazole-containing amino acid for peptide macrocyclisation.
• To evaluate its utility in various peptide synthesis and discovery platforms.

Main Methods:

• Incorporation of the cyanobenzothiazole amino acid via in vitro translation and solid-phase peptide synthesis.
• Assessment of cyclisation efficiency, selectivity, and compatibility with further reactions.
• Molecular dynamics simulations to compare conformational effects with thioether-based methods.

Main Results:

• Rapid and selective macrocyclisation with minimal by-products.
• Compatibility with N-terminal cysteine and further peptide modifications.
• Demonstrated applicability in mRNA display peptide discovery.
• Simulations indicate unique conformational influence due to rigidity and aromatic interactions.

Conclusions:

• The cyanobenzothiazole approach offers a versatile and efficient new strategy for peptide macrocyclisation.
• This method expands the toolkit for designing peptides with improved pharmacological properties.
• It holds significant potential for advancing peptide-based drug discovery and development.