Rapamycin-inspired macrocycles with new target specificity

Nat Chem. 2019 Mar;11(3):254-263. doi: 10.1038/s41557-018-0187-4. Epub 2018 Dec 10.


Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles (named rapafucins) using optimized FKBP-binding domains. Screening of the rapafucin library in human cells led to the discovery of rapadocin, an inhibitor of nucleoside uptake. Rapadocin is a potent, isoform-specific and FKBP-dependent inhibitor of the equilibrative nucleoside transporter 1 and is efficacious in an animal model of kidney ischaemia reperfusion injury. Together, these results demonstrate that rapafucins are a new class of chemical probes and drug leads that can expand the repertoire of protein targets well beyond mTOR and calcineurin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / prevention & control
  • Animals
  • Cell Line
  • Drug Discovery / methods*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Macrolides / chemistry*
  • Macrolides / metabolism*
  • Mice
  • Protective Agents / chemistry*
  • Protective Agents / metabolism*
  • Proteome / metabolism
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control
  • Sirolimus / chemistry
  • Sirolimus / metabolism
  • Swine
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / metabolism
  • Tacrolimus / chemistry
  • Tacrolimus / metabolism
  • Tacrolimus Binding Proteins / chemistry
  • Tacrolimus Binding Proteins / metabolism


  • Macrolides
  • Protective Agents
  • Proteome
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Tacrolimus Binding Proteins
  • Sirolimus
  • Tacrolimus