Chemical modifications of proteins and their applications in metalloenzyme studies.

Methods for residue-selective and stable modification of canonical amino acids enable the installation of distinct functionality which can aid in the interrogation of biological processes or the generation of new therapeutic modalities. Herein, we report an extensive investigation of reactivity and stability profiles for a series of vinylheteroarene motifs. Studies on small molecule and protein substrates identified an optimum vinylheteroarene scaffold for selective cysteine modification. Utilisation of this lead linker to modify a number of protein substrates with various functionalities, including the synthesis of a homogeneous, stable and biologically active antibody–drug conjugate (ADC) was then achieved. The reagent was also efficient in labelling proteome-wide cysteines in cell lysates. The efficiency and selectivity of these reagents as well as the stability of the products makes them suitable for the generation of biotherapeutics or studies in chemical biology.

/pdf/rapid-and-robust-cysteine-bioconjugation-with-1p6lfu5qpg.pdf

Rapid and robust cysteine bioconjugation with vinylheteroarenes

Over the last few decades, design and discovery of chemical reactions that enable modification of proteins at pre-determined sites have been the focus of synthetic organic chemists. As an invaluable tool, the site-and chemoselective functionalization of peptides and proteins offers an exciting opportunity for creating high-value multicomponent conjugates with diverse applications in life sciences and pharmacology. In recent years, multiple strategies have emerged that target natural amino acids directly or convert them into other reactive species for further ligations. However, reactivity and selectivity are still key issues in the current state of chemical modification methodologies. Cysteine is one of the least abundant amino acids and exhibits unique chemistry of the thiol or thiolate group which makes it susceptible to a series of post-translational modifications. The thia-Michael "click" addition reactions, which can proceed under facile conditions provide a promising way for thiol-selective modification of cysteine-containing proteins. In this review, we summarize various reactions for cysteine-selective peptide and protein modification, focus on thia-Michael "click" addition reactions, elaborate on their historical perspective and mechanism, and highlight their applications in modifying biomolecules in a site-specific way.

Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification.

The importance of gem-difunctionalized ketones is represented by their broad applications across chemical boundaries over recent years The interesting reactivities that this class of compounds possess have made them ideal building blocks to access high-value organic molecules Furthermore, the gem-difunctionalized ketone moiety has featured in numerous bioactive molecules For these reasons, a plethora of routes to access such significant molecules have been developed by research groups worldwide - this account looks at delineating the synthesis of gem-difunctionalized ketones from carbonyl substrates, diazo compounds, sulfur ylides and alkynyl reactants

Synthetic Routes Towards the Synthesis of Geminal α-Difunctionalized Ketones

A tyrosine-targeting bioconjugation reaction leads to a Cas9 protein−peptide conjugate that displays a 20-fold increase in cellular delivery.

Protein–Protein Conjugates: Tyrosine Delivers

https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.0c00232

Precise Installation of Diazo-Tagged Side-Chains on Proteins to Enable In Vitro and In-Cell Site-Specific Labeling.

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Precise Installation of Diazo-Tagged Side-Chains on Proteins to Enable In Vitro and In-Cell Site-Specific Labeling.