The stereodynamics of macrocyclic succinimide-thioethers

Area of Science:

• Bioconjugation Chemistry
• Peptide Synthesis
• Stereochemistry

Background:

• Maleimide-thiol coupling is a common bioconjugation method.
• Limited understanding exists regarding the stereoselectivity and stereodynamics of succinimide thioethers in biopolymers.

Purpose of the Study:

• To investigate the stereoselectivity and stereodynamics of succinimide thioethers formed via maleimide-thiol coupling within a peptide macrocycle.
• To explore the influence of the local amino acid environment on succinimide epimerization rates.

Main Methods:

• Macrocyclization of five designed pentapeptides using thiol 1,4-addition to form hexapeptide-sized rings containing succinimide thioethers.
• Analysis of succinimide diastereomer formation and epimerization rates under varying amino acid contexts.

Main Results:

• Both succinimide diastereomers were observed in the macrocyclic peptides.
• The epimerization rate of the succinimide thioether is highly dependent on the adjacent amino acid residues.
• Half-lives for epimerization ranged from hours (with Gly) to weeks (with d-Phe).

Conclusions:

• The local amino acid environment profoundly influences succinimide thioether epimerization.
• This understanding can guide the synthesis of bioconjugates yielding stable and separable diastereomers.