Late Stage Phosphotyrosine Mimetic Functionalization of Peptides Employing Metallaphotoredox Catalysis

Abstract

Access to phosphotyrosine (pTyr) mimetics requires multistep syntheses, and therefore late stage incorporation of these mimetics into peptides is not feasible. Here, we develop and employ metallaphotoredox catalysis using 4-halogenated phenylalanine to afford a variety of protected pTyr mimetics in one step. This methodology was shown to be tolerant of common protecting groups and applicable to the late stage pTyr mimetic modification of protected and unprotected peptides, and peptides of biological relevance.

Optimization of Phosphotyrosine Peptides that Target the SH2 Domain of SOCS1 and Block Substrate Ubiquitination

“…The limited cell permeability maybe overcome by introducing a cell-penetrating sequence, or masking the phosphate group with a prodrug . Enhancing the stability of pTyr against cellular phosphatases may be improved by replacing pTyr with non-hydrolyzable mimetics, − while improving peptide stability may be mitigated by the introduction of strategically positioned amide bond isosteres. In conclusion, the optimized phosphopeptide with potent SOCS1 binding affinity and selectivity against related SOCS-SH2 domain proteins will provide a template for future development of peptidomimetic tools to assist in dissecting the role and potential targets of the SOCS1 SH2-domain in JAK/STAT signaling and developing anti-viral therapeutics.…”

Recent developments in the cleavage, functionalization, and conjugation of proteins and peptides at tyrosine residues

“…Recently, Chen et al developed a visible light photoredox/nickel-catalyzed cross-coupling method for the late-stage functionalization of peptides with phosphotyrosine mimetics, which offers a simpler alternative to previously reported methods utilizing Tyr-protected amino acids. 91 Although this method does not selectively modify Tyr residues, it allows modification of peptides with or without side chain protections, making it highly versatile.…”

Exploring Chemical Modifications of Aromatic Amino Acid Residues in Peptides

“…To this end, Nguyen, Sleebs and co-workers, in 2021, reported a direct Ni-catalyzed C(sp 2 )–C(sp 3 ) cross-coupling reaction between aryl halides 116 and alkyl chlorides under photoredox catalysis to access a variety of phosphotyrosine (pTyr) mimetics 117 (Scheme 31 ). 81 In general, the syntheses of pTyr mimetics involve multistep procedures, and are incompatible with late-stage peptide diversifications. 82 83 However, the reactions proceeded smoothly with protected and unprotected p -halo-Phe amino acid derivatives under the optimized reaction conditions using DMF as the solvent.…”