Details

Autor(en) / Beteiligte

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

Titel

Rapamycin-inspired macrocycles with new target specificity

Ist Teil von

• Nature chemistry, 2019-03, Vol.11 (3), p.254-263

Ort / Verlag

England

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.