Leveraging the ADAM10 prodomain for selective inhibition to enhance recovery after myocardial infarction.

BACKGROUND AND PURPOSE: Inflammation plays a crucial role in the development and progression of numerous acute and chronic diseases such as myocardial infarction (MI) and heart failure. Targeting ADAM proteases, particularly ADAM10, holds promise for fine-tuning inflammatory responses. However, developing selective inhibitors has proven challenging because of cross-inhibition of other metalloproteases. Protein-based inhibitors, such as the synthetic ADAM10 prodomain, offer potential for improved selectivity and effectiveness.

EXPERIMENTAL APPROACH: A novel ADAM10 inhibitor, VTH144, was designed by modifying the ADAM10 prodomain and evaluated empirically for selectivity, efficacy and toxicity both in vitro and in vivo and by using machine learning-based modelling.

KEY

RESULTS

AlphaFold3 predictions confirm that the ADAM10 prodomain is highly selective for its protease and identify VTH144 as a unique ADAM10-inhibiting peptide. Fluorescence resonance energy transfer (FRET) assays verified VTH144 as highly selective for ADAM10, sparing other metalloproteases. In a MI mouse model, we show that VTH144 applied twice, 4 and 48 h after ligation of the left ventricular descending artery (LAD), is highly effective in preserving cardiac function by reducing scar size. VTH144 significantly attenuates ADAM10-mediated CX3CL1 shedding, subsequent neutrophil infiltration into the heart and IL-1β-driven systemic inflammation. Importantly, safety pharmacology in naïve mice revealed that ADAM10 inhibition with VTH144 lacks toxic short-term effects in cardiac, pulmonary, hepatic or renal systems.

CONCLUSIONS AND IMPLICATIONS: Our study highlights the potential of the selective ADAM10 inhibitor VTH144 as a promising therapeutic candidate for improving cardiac function and reducing the risk of heart failure following myocardial infarction.