Developing a new class of anti-amyloid experimental therapeutics in diabetes

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

The research project revolves around characterising the conformations of Amylin (IAPP) suspected of being involved within the pathology of Type II Diabetes. The research will begin with acquainting the research student with the instrumentation employed to effectively understand the dynamic pre-fibrillar conformers of amylin that can form under various solvents and differing conditions to gain an appreciation of the intrinsic nature of the disordered protein and the different structures it adopts on both fibrillar and non-fibrillar pathways.

Once the conformations of aggregation and non-aggregation intermediates have been identified, work will proceed to identify how to direct Amylin from the supposed pathological aggregation pathway toward the non-aggregation pathway via the analysis of potential small molecule binding partners (which may be designed utilising organic synthesis approaches at the bench), peptides (which may be cultivated using synthetic biology methods) and other entities utilising MS techniques.

This research will ideally pave the way toward novel inhibitors for aggregation intermediates identified as the cytotoxic agents implicated in the pathology of Type II Diabetes firstly with in vitro promise. After assessing the promising compound(s) pharmacokinetic/pharmacodynamic parameters and druggability as well as any potential for secondary pharmacology, there may be potential to move forward to testing the compound in vivo using a transgenic murine strain expressing human Amylin, where a Type II Diabetic phenotype may be induced in control and compound treated batches to assess the effects of the novel inhibitor.

Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/N013751/1 01/10/2016 30/09/2025
1654440 Studentship MR/N013751/1 01/10/2015 31/12/2019 Aidan France
 
Title ORIGAMI 
Description ORIGAMI is a multi-component software suite designed to enable semi-autonomous acquisition of activated ion mobility-mass spectrometry (aIMMS) datasets and analysis toolkit to enable more in-depth analysis of biological samples. 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted
Licensed Yes
Impact The software was designed to speed up data acquisition and analysis of complex biological samples. The main areas that ORIGAMI would prove useful is to examine the protein-protein, protein-ligand and protein stability effects, examine differences between biological constructs. In addition, the software was design to enable rapid development of add-ons which can be utilised to improve the analytical workflows.
 
Title ORIGAMI - A software suite for acquisition and interrogation of activated IM-MS datasets 
Description ORIGAMI is a two-component software suite for faster acquisition of activated ion mobility mass spectrometry (IM-MS) datasets and analysis of MS and IM-MS data. The acquisition software (ORIGAMI-MS) works by interfacing MassLynx and Waters Research Enabled Software (WREnS) to carry out a typically tedious task of increasing the collision or cone voltage prior to ion mobility separation. The program works by executing a set of commands that modify various DC potentials in Waters Synapt G2 (and above) family of instruments. There are four acquisition modes available (linear, exponential, Boltzmann and User-defined) which determine the activation ramp parameters. The analysis software (ORIGAMI-ANALYSE) can import single or multiple IM-MS Waters files (.raw) or a list of text files (.csv, .txt) to visualise and interrogate the ion mobility data. It provides an analysis platform to extract, process, visualise and export MS and IM-MS data to a convenient image or text formats. The program was designed to handle activated IM-MS datasets, hence can easily manipulate a large number of files to generate CIU or SID fingerprint maps; datasets can be compared and overlayed to produce high-quality images. All of the processed data can be also exported in an interactive format, to give a webpage-like behaviour with utility tools such as zooming, panning, data hovering and much more. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact ORIGAMI has been widely adopted within the Barran group and has been downloaded and used by other groups interested in studying biologically revelevant samples. 
URL https://github.com/lukasz-migas/ORIGAMI