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, Zhao Li Sun, Jun Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalNature Chemistry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Tacrolimus Binding Proteins
Sirolimus
Calcineurin
Proteins
Equilibrative Nucleoside Transporter 1
Oligopeptides
Macromolecules
Tacrolimus
Screening
Animals
Biological Products
Nucleosides
Cells
Protein Isoforms
Carrier Proteins
Pharmaceutical Preparations
Protein Binding

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Rapamycin-inspired macrocycles with new target specificity. / 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, Zhao Li; Liu, Jun.

In: Nature Chemistry, 01.01.2018.

Research output: Contribution to journalArticle

Guo, Z, Hong, SY, Wang, J, Rehan, S, Liu, W, Peng, H, Das, M, Li, W, Bhat, S, Peiffer, B, Ullman, BR, Tse, CM, Tarmakova, Z, Schiene-Fischer, C, Fischer, G, Coe, I, Paavilainen, VO, Sun, ZL & Liu, J 2018, 'Rapamycin-inspired macrocycles with new target specificity', Nature Chemistry. https://doi.org/10.1038/s41557-018-0187-4
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, Zhao Li ; Liu, Jun. / Rapamycin-inspired macrocycles with new target specificity. In: Nature Chemistry. 2018.
@article{a2cc753e58f248a79287f6ec84c39282,
title = "Rapamycin-inspired macrocycles with new target specificity",
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.",
author = "Zufeng Guo and Hong, {Sam Y.} and Jingxin Wang and Shahid Rehan and Wukun Liu and Hanjing Peng and Manisha Das and Wei Li and Shridhar Bhat and Brandon Peiffer and Ullman, {Brett R.} and Tse, {Chung Ming} and Zlatina Tarmakova and Cordelia Schiene-Fischer and Gunter Fischer and Imogen Coe and Paavilainen, {Ville O.} and Sun, {Zhao Li} and Jun Liu",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41557-018-0187-4",
language = "English (US)",
journal = "Nature Chemistry",
issn = "1755-4330",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Rapamycin-inspired macrocycles with new target specificity

AU - Guo, Zufeng

AU - Hong, Sam Y.

AU - Wang, Jingxin

AU - Rehan, Shahid

AU - Liu, Wukun

AU - Peng, Hanjing

AU - Das, Manisha

AU - Li, Wei

AU - Bhat, Shridhar

AU - Peiffer, Brandon

AU - Ullman, Brett R.

AU - Tse, Chung Ming

AU - Tarmakova, Zlatina

AU - Schiene-Fischer, Cordelia

AU - Fischer, Gunter

AU - Coe, Imogen

AU - Paavilainen, Ville O.

AU - Sun, Zhao Li

AU - Liu, Jun

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85058172244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058172244&partnerID=8YFLogxK

U2 - 10.1038/s41557-018-0187-4

DO - 10.1038/s41557-018-0187-4

M3 - Article

JO - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

ER -