Arun HS KumarUniversity College Dublin, Ireland
Title: Sortilin1 inhibitors as novel therapeutics for tissue fibrosis and vascular calcification
Sortilin1 (SORT1) is a transporter involved in protein sorting and clearance, and its dysregulation is linked to tissue fibrosis and calcification. We assessed the protein- protein network of human SORT1 and its potential as a therapeutic target using small molecules. We identified IGF2R, NTRK2, GRN, and GGA1 as high-affinity interaction networks of SORT1, with IGF2R and GRN regulating tissue fibrosis and microcalcification processes. The high affinity interactions of SORT1 with IGF2R and GRN can be considered as relevant networks in regulating tissue fibrosis or microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and tissue remodelling process. SORT1 is expressed in adipocytes, specialized epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. Using AutoDock Vinaand in-house algorithms, we screened a library of small molecules and established therapeutics for cardiovascular disease and found five drug interaction sites on SORT1 that were targetable at therapeutically feasible concentrations. Empagliflozin, sitagliptin, and lycopene showed superior affinity and concentration affinity ratio (CA) compared to established inhibitors of SORT1. Our findings suggest that targeting SORT1 may be a promising strategy for controlling or reversing cardiovascular fibrosis and calcification. Clinical trials evaluating the efficacy of these compounds are warranted. The novel drug interaction sites identified on SORT1 is currently being explored for developing therapeutic small molecules which are either inhibitors of SORT1 or have dual functionality of interfering with SORT1-IGF2R and/or GRN signalling. This novel therapeutic small molecules development approach to SORT1 and improved formulations of currently approved therapeutics in clinical management of tissue fibrosis and valvular/vascular calcification will be discussed in detail during the presentation.
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