Natural product ligands of FKBP12: Immunosuppressive antifungal agents FK506, rapamycin, and beyond

Abstract

Microorganisms produce natural products as a means of combating competing microorganisms and predators in the soil microenvironment. Modern medicine harnesses these naturally occurring compounds as bioactive agents for drug development. FK506-binding proteins (FKBPs) are enzymes that catalyze cis-trans peptidyl-prolyl isomerization, a key step during protein folding and function. FKBPs are conserved across eukaryotes and can bind natural products to form complexes that inhibit intracellular targets including calcineurin, TOR, and the centrosome-associated protein CEP250. The specificity with which these natural products bind the ubiquitous FKBPs to form protein-drug complexes with exquisite specificity for their targets paved the pathway to develop FK506 (tacrolimus) and rapamycin (sirolimus) and their analogs (pimecrolimus, everolimus, temsirolimus) as FDA approved drugs for transplant recipients, cancer chemotherapy, dermatology, and interventional cardiology. Additionally, because the organisms producing FKBP12 ligands are resident in soil, where natural products can be deployed for survival, this further illustrates why these ligands have potential for development as antimicrobial agents. The goal of this review is to highlight the known and unknown targets of natural product FKBP12 ligands to take stock of advances and further promote research in this area.