A Modular Customizable Ligand-Conjugate (LC) System Targeting Ghrelin O-Acyltransferase

Ghrelin is a 28 amino acid peptide hormone that impacts a wide range of biological processes, including appetite regulation, glucose metabolism, growth hormone regulation, and cognitive function. To bind and activate its cognate receptor, ghrelin must be acylated on a serine residue in a post-translational modification performed by ghrelin <i>O</i>-acyltransferase (GOAT). GOAT is a membrane-bound <i>O</i>-acyltransferase (MBOAT) responsible for the catalysis of the addition of an octanoyl fatty acid to the third serine of desacyl ghrelin. Beyond its canonical role for ghrelin maturation in endocrine cells within the stomach, GOAT was recently reported to be overexpressed in prostate cancer (PCa) cells and detected at increased levels in the serum and urine of PCa patients. This suggests GOAT can serve as a potential route for the detection and therapeutic targeting of PCa and other diseases that exhibit GOAT overexpression. Building upon a ghrelin mimetic peptide with nanomolar affinity for GOAT, we developed an antibody-conjugate-inspired system for customizable ligand-conjugate (LC) synthesis allowing for the attachment of a wide range of cargoes. The developed synthetic scheme allows for the easy synthesis of the desired LCs and demonstrates that our ligand system tolerates an extensive palette of cargoes while maintaining nanomolar affinity against GOAT.