Hydrophobic Tag‐Assisted Scalable Synthesis of Trofinetide and Its GPE Analogues
Abstract
Trofinetide (H-Gly-α-MePro-Glu-OH), an FDA-approved drug for Rett syndrome, is a modified derivative of the neuroprotective tripeptide glypromate (H-Gly-Pro-Glu-OH; GPE). We report a scalable, high-yielding liquid-phase peptide synthesis (LPPS) route employing (2,4-bis(octadecyloxy)phenyl)methanol (Tag-OH) as a hydrophobic auxiliary. The method is compatible with both linear and convergent paradigms, with process mass intensity (PMI) analysis confirming the superior efficiency of the convergent approach. In addition to establishing a robust process for trofinetide, the strategy enabled synthesis of two novel non-natural GPE analogues, H-Gly-Aib-Glu-OH and H-Gly-Aib-Asp-OH. This tag-assisted LPPS provides a greener alternative to existing routes and offers a versatile platform for industrial production of short-chain oligopeptides.
Fields of Study & Subjects
Chemical Synthesis and Analysis
Peptidase Inhibition and Analysis
Carbohydrate Chemistry and Synthesis
Publication details
- Journal / source
- Journal of Peptide Science
- Publisher
- Wiley
- Volume
- 32
- Issue
- 6
- Pages
- e70096–e70096
- Publication date
- 1 January 2026
- Language
- EN