Many cardiovascular healthy diets contain bioactive, electrophilic natural products that covalently modify enzymes, redox-sensing proteins and transcription factors, affording long-lasting effects on cellular function and behaviour.1 Our research focusses on characterising the molecular mechanisms of electrophilic natural products that are reported to exhibit interesting therapeutic properties and excellent safety features in the treatment of stroke, thrombosis and diabetes.
Recently, we screened platelets with a library of naturally occurring isothiocyanates with the aim to exploit the untapped cysteinome in platelets. Leveraging the power of activity-based protein profiling (ABPP) technology,2 protein disulfide isomerases (PDIs) were identified as the dominant targets modulated by these natural products in a covalent fashion, leading to attenuation of their enzymatic activity in disulfide reduction assays. By comparing these isothiocyanates with potent pan-PDI inhibitors, we showed that PDI inhibition are antithrombotic in vitro and in vivo by impeding PDI-catalysed oxidative folding of integrin aIIb3.
Importantly, our data provides evidence that these active isothiocyanate compounds can selectively modulate platelets’ response to thrombotic stimuli without influencing their haemostatic function. Our research also highlights the exciting potential in exploiting electrophilic natural products as target discovery tools.