Selenazolidine: a selenium containing proline surrogate in peptide science

Area of Science:

• Peptide Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Limited options exist for incorporating selenium into peptides beyond selenocysteine (Sec) and selenomethionine (SeMet).
• Non-natural amino acids offer opportunities to expand peptide functionalities and applications.
• Proline analogs are crucial in peptide structure and function.

Purpose of the Study:

• To investigate l-4-selenazolidine-carboxylic acid (selenazolidine, Sez) as a novel proline analog for peptide synthesis.
• To develop and optimize protocols for incorporating Sez into peptide sequences using standard solid-phase peptide synthesis (SPPS) strategies.
• To evaluate the stability and functional impact of Sez substitution in bioactive peptides.

Main Methods:

• Synthesis of Sez-containing model tripeptides using Boc/Bzl and Fmoc/tBu SPPS strategies in solution and on solid support.
• Optimization of generic protocols for Sez incorporation, including the use of an Fmoc-Xxx-Sez-OH dipeptide building block.
• Preparation and characterization of a vasopressin receptor-1A antagonist analog with Sez replacing proline.

Main Results:

• Successful incorporation of Sez into peptides using optimized Fmoc/tBu SPPS protocols.
• Sez residue demonstrated stability under basic conditions relevant to peptide synthesis.
• Sez-containing vasopressin analog exhibited comparable pharmacological properties and endopeptidase stability to its proline counterpart.

Conclusions:

• Selenazolidine (Sez) is a viable proline surrogate for peptide synthesis, offering a new method for selenium incorporation.
• Sez can be readily incorporated using standard SPPS, expanding the toolkit for peptide chemists.
• Sez holds potential as a selenium probe for analytical techniques like NMR and mass spectrometry, complementing Sec and SeMet.