Probing the extraordinary bioactivity of macrocyclic natural products: privileged motifs or biosynthetic artefacts?

Lead Research Organisation: University of Leeds
Department Name: Sch of Chemistry

Abstract

The fields of Chemical Biology and Medicinal Chemistry require collections of molecules which are likely to be biogically active. Such collections can be screened to identify small molecules which interact with biological molecules such as proteins. Such small molecules can reveal fundamental insights into biological processes and can sometimes be ultimately used to treat diseases.The grant will explore the fundamental principles which chemists can use to design collections of small molecules. Naturally occurring small molecules, known as natural products, are necessarily biologically active. Many of these molecules have large cyclic structures. This grant will explore whether this type of structure predisposes small molecules towards biological activity.A collection of natural product-like small molecules will be prepared by extending diversity-oriented chemistry which has been developed through Professor Nelson's EPSRC Advanced fellowship. Some of these molecules will have large cyclic structures, and others will not. The molecules will be screened for a broad range of biological activities. By comparing the biological profiles of the classes of molecules, we will be able to address the fundamental chemical question of whether macrocyclic molecules are fundamentally predisposed towards biological activity. In addition, the grant will encourage postdoctoral mobility between physical and life sciences, and sufficient priority for EPSRC issued to issue a recent call.

Publications

10 25 50
 
Description Robust methods for the preparation of natural product-like macrocycles have been developed (an under-represented structural class in screening collections).
Exploitation Route Compounds based on the scaffolds have been screened by both pharmaceutical companies and academic chemical biology units.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Compounds based on the macrocyclic scaffolds have been evaluated for biological function through a pharmaceutical company open innovation scheme
First Year Of Impact 2015
Sector Pharmaceuticals and Medical Biotechnology
 
Description EPSRC programme grant
Amount £2,700,000 (GBP)
Funding ID EP/N013573/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 01/2021
 
Description IMI European Lead Factory
Amount € 1,600,000 (EUR)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 01/2013 
End 12/2017
 
Description AZ screening 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Screening compounds
Collaborator Contribution HT screening
Impact None yet
Start Year 2014
 
Description MPI 
Organisation Max Planck Society
Department Max Planck Institute for Molecular Physiology
Country Germany 
Sector Public 
PI Contribution Screening compounds
Collaborator Contribution HT screening and follow-up biology
Impact None to date
Start Year 2014
 
Description PPIs 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016
 
Description PPIs 
Organisation Domainex
Country United Kingdom 
Sector Private 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016
 
Description PPIs 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016