Highly Reactive and Tracelessly Cleavable Cysteine‐Specific Modification of Proteins via 4‐Substituted Cyclopentenone

Abstract

A rapid and cysteine-specific modification of proteins using 4-substituted cyclopentenone via a Michael addition tandem elimination reaction was developed. Compared to the classical method, this reaction featured fast kinetics with a stable product. More importantly, this conjugation could be tracelessly removed by exchange with a Michael addition donor. The conjugation and regeneration process not only exhibited little change to the structures or conformations of the proteins but also exhibited little disturbance to their biological functions, such as their enzymatic activities.

A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

“…1 Thus, multiple approaches have been developed to selectively modify endogenously reactive amino acid residues in proteins. [2][3][4][5] Chemo-selective reactions on particular residues in proteins are broadly utilized, including cysteine, [6][7][8][9] lysine, [10][11][12][13][14][15] tyrosine, 16 tryptophan, 17 arginine 18 and methionine. 19,20 The development of chemical tools for siteselective protein labeling is in high demand due to its high precision and versatility.…”

Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide

“…Multiple approaches have been developed to selectively modify the specific amino acid residues of proteins, including chemo‐selective reactions, ligand‐induced protein conjugation, etc [33–42] . Cysteine is lowly abundant and with unique reactivity, which makes it the most used residue for protein modification [43–48] . Peptide modulators provide a streamlined approach for interrupting PPIs [49–51] .…”

“…[33][34][35][36][37][38][39][40][41][42] Cysteine is lowly abundant and with unique reactivity, which makes it the most used residue for protein modification. [43][44][45][46][47][48] Peptide modulators provide a streamlined approach for interrupting PPIs. [49][50][51] We recently developed a peptide cyclization strategy via bis-alkylation between Cys and Met.…”

Chemoselective and photocleavable cysteine modification of peptides and proteins using isoxazoliniums

“…Development of bioconjugates with cleavable linkers has recently been recognized as an emerging area in chemical biology due to their versatile applications in drug development, proteomics, and in vivo imaging 31 . Among the reported cysteineselective modifications, only a few of them are cleavable, such as electron-deficient alkynes reported by our group 15 , 5-methylene pyrrolones reported by Zhou 24 , and 4-substituted cyclopentenones reported by Yin 25 . However, all of those methods are of thiol-induced cleavage and the bioconjugates may undergo exchange reactions with thiols in plasma, limiting their applications in in vivo studies 32,33 .…”

“…Conventional approaches for cysteine modification relied on α-halocarbonyls (via S N 2 reaction) and maleimides (via Michael addition). However, the relatively low chemoselectivity of α-halocarbonyls and potential hydrolysis of the maleimide-based conjugates prompted the development of a number of metal-free and transition metalmediated cysteine modifications in the past decade by Davis, Bernardes, Pentelute, our group, and others [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] . Despite those advances, it is of ongoing interest to develop new cysteine modification methods with high efficiency, excellent selectivity, and using easily accessible reagents under mild reaction conditions.…”