The Role of Thiol-Cysteine Sensitivity in Modulating the Bioavailability and Efficacy of Drug Candidates

Thiols are essential biomolecules involved in many biological processes, including redox regulation and signal transduction. Thiols are ubiquitous in biological systems and can be reversibly modified by electrophilic compounds through a mechanism known as the “thiol switch.”1 Thiol sensitivity has emerged as a promising approach for modulating the pharmacological properties of drug candidates.2 Recently, conjugation strategies have been developed to take advantage of thiol- sensitivity for enhancing drug bioavailability and efficacy. Here, we investigate the role of thiol- sensitivity in modulating the bioavailability and efficacy of drug candidates using an aspirin-cysteine conjugate. Aspirin is a well-known anti-inflammatory agent (NSAID), and cysteine is an amino acid that contains a thiol group and is involved in redox signaling and other important cellular processes. The conjugate was synthesized using a thioester linkage, which can act as a thiol switch that is sensitive to changes in the redox environment of the cell.3 The bioavailability and efficacy of the conjugate were evaluated in vitro. The synthesis of the aspirin-cysteine conjugate was confirmed using nuclear magnetic resonance (NMR) spectroscopy, which showed the successful linkage of aspirin and cysteine through a thiol-cleavable linker. In vitro assays demonstrated that the aspirin-cysteine conjugate had higher stability and longer half-life compared to aspirin alone. These results suggest that thiol- sensitivity of drug conjugates have the potential to enhance bioavailability and efficacy.