TANGO1 inhibitors limit tissue scarring

Scarring is a normal outcome of the wound healing program, but excessive secretion of ECM proteins such as collagen can lead to fibrosis and compromise tissue function. Despite the widespread occurrence of fibrosis, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We designed membrane permeant-peptide inhibitors that specifically target and disrupt the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Dissociation of the TANGO1 and cTAGE5 complex leads to their partial degradation and a consequent inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish resulted in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduced secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, this targeted interference in the TANGO1-cTAGE5 binding interface enables therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.