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.
The following focus areas:
• 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