Format

Send to

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

Rapamycin-inspired macrocycles with new target specificity.

Author information

1
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
2
The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
3
Rapafusyn Pharmaceuticals, Baltimore, MD, USA.
4
The Scripps Research Institute, La Jolla, CA, USA.
5
HiLIFE and Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
6
Institute of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
7
Food and Drug Administration, Rockville, MD, USA.
8
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
9
Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
10
Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
11
Department of Enzymology, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
12
Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
13
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. joliu@jhu.edu.
14
The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD, USA. joliu@jhu.edu.

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.

PMID:
30532015
PMCID:
PMC6435255
[Available on 2019-06-10]
DOI:
10.1038/s41557-018-0187-4
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center