Enabling Peptide Ligation at Aromatic Junction Mimics via Native Chemical Ligation and Palladium-Mediated S-Arylation

Abstract

Published as part of the Organic Letters virtual special issue "Chemoselective Methods for Labeling and Modification of Peptides and Proteins".

Chemical Engineering of Artificial Transcription Factors by Orthogonal Palladium(II)‐Mediated S‐Arylation Reactions

“…We have recently combined NCL and palladium(II)‐mediated Cys arylation chemistry to enable effective peptide ligation at aromatic junctions [24] . This combination enabled a practical strategy to assemble peptides at aromatic junctions such as Tyr and Phe.…”

“…We have recently combined NCL and palladium(II)mediated Cys arylation chemistry to enable effective peptide ligation at aromatic junctions. [24] This combination enabled a practical strategy to assemble peptides at aromatic junctions such as Tyr and Phe. To test the applicability of our approach for the total chemical protein synthesis of modified proteins, we decided to synthesize a stapled version of the DNA-binding domain of Max TF using NCL and the orthogonal palladium(II) strategy (Figure 5B).…”

Site-Specific Acetylation of the Transcription Factor Protein Max Modulates Its DNA Binding Activity

“…The precise influence of altering the acetylation marks of TFs’ binding activity in these diseases is yet to be explored. We anticipate this demonstration to prepare homogeneous synthetic TFs with the desired PTM pattern to pave the way for further studies to dissect crosstalk between Max-PTMs and other essential bHLH-TFs as well as design new analogs with refined activity. − Importantly, given the different PTM levels and sites that are already identified in Max, − , a potential interplay between Max phosphorylation and acetylation can possibly represent an additional regulatory role in controlling the bHLH Myc/Max TF network, which requires further investigation. Finally, we envision that the synergy between total chemical synthesis and high-throughput technology will not only provide profound predictive insights into the impact of PTMs on the binding of additional oncogenic TFs to DNA but also lay the groundwork for comprehending other essential oligonucleotide-binding proteins of physiological significance.…”

Synthetic Peptides: Promising Modalities for the Targeting of Disease‐Related Nucleic Acids

“…[65] Several solid phase peptide synthesis (SPPS) approaches have been used to produce Omomyc [27][28][29]31] (as well as Myc and Max). [30,[66][67][68] Brown et al synthesized the whole protein using either microwave or infrared irradiation during SPPS and also explored native chemical ligation (NCL) to be able to make Omomyc from two fragments. Furthermore, they developed a high-throughput microbial expression workflow to introduce mutations and improve Omomyc binding affinity.…”