Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs

In the period 1998 to 2003, a number of reviews have appeared evaluating the potential of rapamycin and other immunophilin ligands as therapies for cancer, organ transplantation, restenosis prevention, autoimmune disorders, and neurodegenerative diseases. This review aims to evaluate advances in the field since that time, specifically detailing progress in: (i) the role of rapamycin in inhibiting its principal cellular target, the mammalian target of rapamycin (mTOR) in both of its protein complexes, (ii) understanding the role of specific genes in the mechanism of rapamycin biosynthesis, (iii) the production of novel analogs of rapamycin via precursor-directed biosynthesis, (iv) the enzymology of the pipecolate incorporating enzyme (RapL) in vitro, and (v) the pharmacology and mechanistic chemical biology of rapamycin analog mediated neuroprotection and neuroregeneration.