Formyl benzeno boronic acids rapidly and selectively react with N-terminal cysteines to yield a reversible boronated thiazolidine that may be used in the interactive orthogonal modification of peptides.
Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N‐hydroxysuccinimide (NHS) activated esters, are combined in NHS‐activated acrylamides for efficient chemoselective amino‐sulfhydryl stapling on native peptides and proteins. NHS‐activated acrylamides allow for a fast functionalization of N‐terminal cysteines (k2=1.54±0.18×103 M−1 s−1) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross‐linking of in‐chain or C‐terminal cysteines with nearby lysine residues. NHS‐activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual‐modifications. This strategy was successfully applied to the late‐stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS‐activated acrylamides is expected to promote amino‐sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.
The development of metal-based anticancer drugs has been hampered, among other reasons, by their lack of selectivity for cancer cells. In a recent article, Zou and co-workers presented the successful intracellular activation of organogold(I) complexes for potential cancer treatment through Pd(II)-mediated transmetallation, overcoming some off-target activity of novel gold-based drugs. This unique strategy builds the perfect bridge between metallodrug usage and bioorthogonal intracellular catalysis for more advanced and selective therapies. Such an approach will hopefully pave the way for forthcoming studies in medicinal inorganic chemistry.
The development of bioconjugation chemistry has enabled the combination of various synthetic functionalities to proteins, giving rise to new classes of protein conjugates with functions well beyond what Nature can...
Correction for ‘Iminoboronates are efficient intermediates for selective, rapid and reversible N-terminal cysteine functionalisation’ by Hélio Faustino et al., Chem. Sci., 2016, 7, 5052–5058.
A methodology for the synthesis of sulfonyl hydrazides mediated by hypervalent iodine is described. Taking advantage of the umpolung properties of hypervalent iodine reagents, the polarity of sodium sulfinate salts...
N-terminal Cys modification has been intensively studied to produce homogeneous bioconjugates essentially through two modes of reaction: reversible modification with the equilibrium shifted towards the formation of the desired conjugate or stable and irreversible conjugates. Herein, we report a new method of N-terminal cysteine modification using O-salicylaldehyde esters (OSAEs) through fast conjugation and irreversible deconjugation. These reagents can rapidly react with N-terminal Cys at low-micromolar concen-tration to form thiazolidines with subsequent hydrolysis of the ester moiety to the phenolic derivative. These phenolic thiazolidines can be hydrolyzed at acidic pH ( � 4.5) to recover the intact N-terminal Cys. Bioconjugation reactions using OSAEs offer controlled reversibility to as act as a protecting group for N-terminal cysteines, allowing the modification of in-chain residues without perturbing the N-terminal Cys, which can then be deprotected and used as a conjugation site.
Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N‐hydroxysuccinimide (NHS) activated esters, are combined in NHS‐activated acrylamides for efficient chemoselective amino‐sulfhydryl stapling on native peptides and proteins. NHS‐activated acrylamides allow for a fast functionalization of N‐terminal cysteines (k2=1.54±0.18×103 M−1 s−1) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross‐linking of in‐chain or C‐terminal cysteines with nearby lysine residues. NHS‐activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual‐modifications. This strategy was successfully applied to the late‐stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS‐activated acrylamides is expected to promote amino‐sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.
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