Research Topic

Cysteine Biochemistry in Drug Pharmacology

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About this Research Topic

Cysteine is a highly conserved and a versatile amino acid that is least abundant in the cellular proteome. It confers distinct biochemical properties on enzymes & proteins due mostly to the presence of a thiol group (-SH) which allows cysteine to assume a range of valence states -2 to +6 to catalyze a myriad of chemistries. Upon deprotonation, the thiol group generates a much reactive thiolate nucleophile (-S-) that can readily engage with electrophilic warheads, a phenomenon that has been used in the development of cysteine-targeted small molecule therapeutics. In addition, the thiolate nucleophile also makes cysteine highly susceptible to direct post translational modifications (PTMs) with reactive oxygen, nitrogen and sulfur species (ROS, RNS, RSS) thus modulating the properties of the protein/clinical biomarker itself. The impact of this unique sulfur chemistry to not only functionally alter the kinetics of a biomarker through direct PTM but also to enable development of targeted small & large molecule therapies renders cysteine of highest pharmacological significance.

This application of cysteine chemical biology particularly in context of drug discovery & development has not been covered in the Frontiers in Pharmacology Journal and as such the goal of this Research Topic is to highlight the unique relevance of this amino acid in driving drug pharmacology through some of the following focus areas:

• Redox cysteine modifications of clinical biomarkers/targets including redox sensors, transcription factors through oxidation, nitrosylation & sulfation eg. kinases and non-kinases
• Irreversible and reversible covalent cysteine inhibition of clinical targets eg. BTK, EGFR, JAK, etc.
• Application of di- and tri-sulfides to the quality of monoclonal antibodies/biologics & biosimilars product eg. role of disulfide isoforms of IgG1, IgG2 on the quality of biologics, kinetics of trisulfide formation and impact on stability of the monoclonal antibody
• Targeted/site-specific conjugations in ADCs and cysteine based chemical cross-linkers
• In-silico and computational approaches to predict reactive cysteines for drug targeting eg. catalytic vs non-catalytic, structural, etc.
• ABPP/Reactivity-based chemoproteomics profiling including cysteine-reactive fragment based drug discovery
• Targeting mutations of amino acid residues to cysteine in the disease/clinical biomarkers and also acquired Cys-to-Ser resistance mutations in response to cysteine-directed drugs


Topic Editor Dr Jones is employed by Jnana Therapeutics, Dr Junutula is employed by Cellerant Therapeutics and Dr Wani is employed by Pfizer (United States). All other Topic Editors declare no competing interests with regards to the Research Topic subject.


Keywords: Cysteine, covalent drugs, oxidation, conjugation, di- and trisulfide


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Cysteine is a highly conserved and a versatile amino acid that is least abundant in the cellular proteome. It confers distinct biochemical properties on enzymes & proteins due mostly to the presence of a thiol group (-SH) which allows cysteine to assume a range of valence states -2 to +6 to catalyze a myriad of chemistries. Upon deprotonation, the thiol group generates a much reactive thiolate nucleophile (-S-) that can readily engage with electrophilic warheads, a phenomenon that has been used in the development of cysteine-targeted small molecule therapeutics. In addition, the thiolate nucleophile also makes cysteine highly susceptible to direct post translational modifications (PTMs) with reactive oxygen, nitrogen and sulfur species (ROS, RNS, RSS) thus modulating the properties of the protein/clinical biomarker itself. The impact of this unique sulfur chemistry to not only functionally alter the kinetics of a biomarker through direct PTM but also to enable development of targeted small & large molecule therapies renders cysteine of highest pharmacological significance.

This application of cysteine chemical biology particularly in context of drug discovery & development has not been covered in the Frontiers in Pharmacology Journal and as such the goal of this Research Topic is to highlight the unique relevance of this amino acid in driving drug pharmacology through some of the following focus areas:

• Redox cysteine modifications of clinical biomarkers/targets including redox sensors, transcription factors through oxidation, nitrosylation & sulfation eg. kinases and non-kinases
• Irreversible and reversible covalent cysteine inhibition of clinical targets eg. BTK, EGFR, JAK, etc.
• Application of di- and tri-sulfides to the quality of monoclonal antibodies/biologics & biosimilars product eg. role of disulfide isoforms of IgG1, IgG2 on the quality of biologics, kinetics of trisulfide formation and impact on stability of the monoclonal antibody
• Targeted/site-specific conjugations in ADCs and cysteine based chemical cross-linkers
• In-silico and computational approaches to predict reactive cysteines for drug targeting eg. catalytic vs non-catalytic, structural, etc.
• ABPP/Reactivity-based chemoproteomics profiling including cysteine-reactive fragment based drug discovery
• Targeting mutations of amino acid residues to cysteine in the disease/clinical biomarkers and also acquired Cys-to-Ser resistance mutations in response to cysteine-directed drugs


Topic Editor Dr Jones is employed by Jnana Therapeutics, Dr Junutula is employed by Cellerant Therapeutics and Dr Wani is employed by Pfizer (United States). All other Topic Editors declare no competing interests with regards to the Research Topic subject.


Keywords: Cysteine, covalent drugs, oxidation, conjugation, di- and trisulfide


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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