1. Rapamycin-inspired macrocycles with new target specificity
- Author
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Wukun Liu, Sam Y. Hong, Zhaoli Sun, Brett R. Ullman, Jingxin Wang, Zlatina Tarmakova, Shridhar Bhat, Zufeng Guo, Ville O. Paavilainen, Manisha Das, Brandon J. Peiffer, Wei Li, Shahid Rehan, Imogen R. Coe, Cordelia Schiene-Fischer, Hanjing Peng, Gunter Fischer, Jun O. Liu, Chung Ming Tse, and Institute of Biotechnology
- Subjects
0301 basic medicine ,Proteome ,CYCLOSPORINE-A ,Swine ,General Chemical Engineering ,EQUILIBRATIVE NUCLEOSIDE TRANSPORTER ,116 Chemical sciences ,PROTEIN ,ISCHEMIA-REPERFUSION INJURY ,Equilibrative nucleoside transporter 1 ,Protective Agents ,01 natural sciences ,Article ,Tacrolimus ,CALCINEURIN ,Cell Line ,HIGH-AFFINITY ,Tacrolimus Binding Proteins ,03 medical and health sciences ,Mice ,IMMUNOSUPPRESSANT FK506 ,FUNCTIONAL-CHARACTERIZATION ,BINDING ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Sirolimus ,biology ,010405 organic chemistry ,Effector ,Chemistry ,TOR Serine-Threonine Kinases ,ADENOSINE RECEPTORS ,Equilibrative nucleoside transporter ,General Chemistry ,Acute Kidney Injury ,0104 chemical sciences ,Calcineurin ,030104 developmental biology ,FKBP ,Biochemistry ,Reperfusion Injury ,biology.protein ,Macrolides ,Nucleoside - Abstract
Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action—they form binary complexes with FKBP through a shared FKBP-binding domain before forming ternary complexes with their respective targets, 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 that are 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 ischemia 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., Graphical abstract
- Published
- 2023