Rapamycin-inspired macrocycles with new target specificity

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Guo , Z , Hong , S Y , Wang , J , Rehan , S , Liu , W , Peng , H , Das , M , Li , W , Bhat , S , Peiffer , B , Ullman , B R , Tse , C-M , Tarmakova , Z , Schiene-Fischer , C , Fischer , G , Coe , I , Paavilainen , V O , Sun , Z & Liu , J O 2019 , ' Rapamycin-inspired macrocycles with new target specificity ' , Nature Chemistry , vol. 11 , no. 3 , pp. 254-263 . https://doi.org/10.1038/s41557-018-0187-4

Title: Rapamycin-inspired macrocycles with new target specificity
Author: 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.
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2019-03
Language: eng
Number of pages: 10
Belongs to series: Nature Chemistry
ISSN: 1755-4349
URI: http://hdl.handle.net/10138/325533
Abstract: 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.
Subject: 116 Chemical sciences
EQUILIBRATIVE NUCLEOSIDE TRANSPORTER
ISCHEMIA-REPERFUSION INJURY
FUNCTIONAL-CHARACTERIZATION
ADENOSINE RECEPTORS
IMMUNOSUPPRESSANT FK506
CYCLOSPORINE-A
HIGH-AFFINITY
BINDING
PROTEIN
CALCINEURIN
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