title: Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds.
abstract: Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These "clients" include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the "undruggable" features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School , 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, United States.|Department of Pharmaceutical Chemistry, University of California at San Francisco , 675 Nelson Rising Lane, San Francisco, California 94158, United States.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Dunyak
authors.affiliation: Department of Pharmaceutical Chemistry, University of California at San Francisco , 675 Nelson Rising Lane, San Francisco, California 94158, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D020123:Sirolimus / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus