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Development of ArgTag for Scalable Solid-Phase Synthesis of Aggregating Peptides
Vincent Freiburghaus1, Aliénor Jeandin1, Łukasz Frankiewicz2
1Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
ACS Chemical Biology
|October 23, 2025
Summary
A new hexaarginine tag (ArgTag) simplifies peptide synthesis by preventing aggregation during solid-phase peptide synthesis (SPPS). This method improves peptide purity and is effective on various resins and larger scales.
Area of Science:
- Biochemistry
- Organic Chemistry
- Chemical Biology
Background:
- Solid-phase peptide synthesis (SPPS) is hindered by peptide aggregation, leading to reduced efficiency and purity.
- Previous synthesis tags (SynTag) aided chemical protein synthesis but required simplification for broader application.
- Short, aggregation-prone peptide sequences present unique challenges in SPPS.
Purpose of the Study:
- To develop a simplified hexaarginine tag (ArgTag) for aggregation suppression in SPPS.
- To refine enzymatic tag removal for mild and efficient cleavage.
- To demonstrate the ArgTag's efficacy across diverse resins, loadings, and scales.
Main Methods:
- Development of a simplified C-terminal hexaarginine tag (ArgTag).
- Refinement of enzymatic removal using Carboxypeptidase B under mild, linker-free conditions.
- Evaluation of ArgTag on six different solid supports (resins) using automated fast-flow SPPS (AFPS).
Main Results:
- Consistent aggregation suppression and improved crude peptide purities were observed across all tested resin types.
- The ArgTag proved effective on various resin polarities and loadings.
- Successful demonstration of ArgTag efficiency on a larger scale with economical synthesis parameters.
Conclusions:
- The ArgTag strategy effectively broadens the applicability of SynTag to short, difficult peptide sequences.
- This approach offers a scalable solution to enhance SPPS efficiency for challenging peptide targets.
- The simplified tag and enzymatic removal provide a practical advancement in peptide synthesis methodology.
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