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 O-acyltransferase (GOAT). GOAT is a membrane bound O-acyltransferase (MBOAT) responsible for 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 detection and therapeutic targeting for PCa and other diseases which 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 (LCs) synthesis allowing for attachment of a wide range of cargos. The developed synthetic scheme allows for facile synthesis of desired LCs and demonstrates our ligand system tolerates an extensive palette of cargos while maintaining nanomolar affinity against GOAT.