Rapamycin-inspired macrocycles with new target specificity

Zufeng Guo, Sam Y. Hong, Jingxin Wang, Shahid Rehan, Wukun Liu, Hanjing Peng, Manisha Das, Wei Li, Shridhar Bhat, Brandon Peiffer, Brett R. Ullman, Chung Ming Tse, Zlatina Tarmakova, Cordelia Schiene-Fischer, Gunter Fischer, Imogen Coe, Ville O. Paavilainen, Zhaoli Sun, Jun O. Liu

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)254-263
Number of pages10
JournalNature Chemistry
Issue number3
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)


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