Available Technology
A fragment based drug discovery platform ; For high throughput synthesis and screening of protein-protein inhibitors
Technology:
The present technology describes a Fragment Based Drug Discovery platform that combines the use of NMR spectroscopy and computational model to better build a library of protein inhibitors. The first step uses NMR spectroscopy to generate a large library of 3-D linking fragments that will bind to target proteins; followed by high throughput in silico screening procedures to identify optimal protein binders with additional functionalities and geometries. Selected peptides are then synthesized by solid phase peptide synthesis or by in vitro synthesis and again screened by a variety of assays that will identify protein-protein interactions (e.g. FRET, Reverse Two-Hybrid, fluorescence polarization or pull-down). Finally, the best protein-protein interaction inhibitors are identified by a combination of deconvolution synthesis and mass spectrometry methods. Proof of concept of this technology has been demonstrated with generation of a compound library for the immunomodulators, calcineurin inhibitors.
Markets Addressed
Fragment based drug discovery (FBDD) methods chemically link or extend known small molecule binders to construct high-affinity inhibitors of protein interactions. The initial binding fragments are readily identified by various biophysical methods, including Nuclear Magnetic Resonance (NMR) spectroscopy. Common NMR methods include Saturation Transfer Difference (STD) or water Logsy in combination with Inter-Ligand nuclear Overhauser Enhancement (iLOE) experiments. One major challenge for FBDD is that it is very difficult to construct a ‘perfect’ linker or fragment extension that contributes positively to the free energy of binding. Successful linking of two fragments has very rarely been accomplished in practice, even when a high resolution structure of the protein-fragments complex is available.
It is therefore highly desirable that fragment linking and fragment extension is coupled with facile high throughput synthesis and screening methods. Another challenge of FBDD is that the extended or linked fragments often do not exhibit a sufficiently complex 3-dimensional shape to bind and inhibit protein-protein interaction (PPI) surfaces.
Innovations and Advantages
The present invention enables generation of a large number of rigid compounds that incorporate one or more protein binding fragments in a large number of three dimensional orientations, while presenting ample additional functionalities and geometries for interaction with the target protein.
As a proof of concept, this novel drug discovery platform was applied for the discovery of new protein inhibitors of the oncogenic complex MCT-1/DENR and the immunomodulatory complex calcineurin/NFAT.
However, this technology has the potential to be applied towards the discovery of countless therapeutic leads.
Additional Information
Intellectual Property Status: Patent(s) pending
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Inventor(s):
Arthanari, Haribabu
Fahmy, Amr F.
Gelev, Vladimir M.
Hagner, Patrick R.
Rodriguez-Mias, Ricard A.
Wagner, Gerhard
Categories:
For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #4717