Protein-Protein Interaction Inhibitors: From Design and Synthesis, Through Biophysics to Cell Permeable Inhibitors

Lead Research Organisation: Imperial College London
Department Name: Chemistry


The development of new medicines relies upon the ability of scientists to understand the biological details of a disease and also the way in which new molecular medicines can be designed to either cure the illness or alleviate its symptoms. One very important biological mechanism is the way in which one protein recognises and binds to another protein in order to regulate its function. This functional regulation by protein-protein interactions underpins most of the biological activity in living cells, and yet we do not understand what properties of a protein allow it to bind to another, nor do we understand how to design molecules to prevent or enhance such interactions. Gaining such an understanding would be a huge advance. It is estimated that there are approximately 650,000 types of specific protein-protein interactions in each human cell. This means that there are potentially 650,000 targets for modifying biological function by the use of drugs. Essentially every part of the biological process, and therefore every disease, could in principle be addressed by such drugs. Although the knowledge of how to do this remains beyond our grasp, progress has been made in some parts of the problem, and new ways of looking at the problem have also been developed with others already in development. This research network has the aim of bringing the whole UK community engaged in this type of research together, and in particular connecting the scientists in universities and research institutes with the scientists in biotechnology and pharmaceutical companies to pool their intellectual and technical capabilities. In doing this we have two main aims in mind. Firstly the sharing of knowledge so that everyone has a wider picture of what is now possible and understood and what still needs to be learned and discovered. Secondly the formulation of a UK-wide plan to solve the outstanding problems in this area with the intention of accelerating the development of new drugs for serious illnesses by connecting together progress made by the various research teams across the UK.

Planned Impact

Pathways to Impact Summary

UK research councils, charities and industry all invest in research on protein-protein interactions but the many scientific challenges within this field are each, multifaceted, multidisciplinary and interlinked.
The purpose of the network is therefore to increase the impact of the funding already in place and to define a landscape that will assist in helping future funding to have the maximum impact. This means impact both on the field of PPI research and on the ultimate fruition of this research which is the discovery, subsequent development and successful deployment of new drugs to the benefit of public health and the UK economy.
This proposal focuses on a challenge of major relevance to modern day healthcare. Protein-protein interactions represent a target class for molecular therapeutics that far exceeds the chemical and biological space which the scientific community is capable of addressing. This is relevant to a number of end users
(a) The academic community
(b) The pharmaceutical industry
(c) The systems biology community
(d) Clinicians
A specific objective of this call is the development of better links between industry and academia in the area of chemical biology. These end-users will directly benefit from access to the leading academics in the area of PPIs and the opportunity to define the scientific agenda in partnership. At a societal level, we recognize this network call as an opportunity to explore and develop a cultural change within the scientific community - better interaction with users across the entire spectrum of the translational healthcare community.
Beyond new research activity, funding agencies and learned societies will have access to the outputs of the network (e.g. the PPI Roadmap) and this will benefit the entire user community from the academic through to policy makers as a document that influences the future scientific and funding agenda.


10 25 50
Description Key PPI Capabilities in the UK

We have in the UK an even spread of scientists involved in modelling, making molecules and measuring biological outcomes. Most scientists have access to the entire toolkit' required for PPI investigational science either directly within their own labs or by collaboration . Only those in large pharma have integrated access to all three components of the toolkit, and there have been requests within the surveys for those outside of industry structures to have access to such capabilities.

Capturing current collaborations in progress within the UK, we find collaborations between 26 universities, 5 institutions and 25 companies, both large and small. Network maps of the connections between academic groups, SMEs and Pharma in the UK and to global groups are given below and can also be found on the PPI-Net website

Current funding and support in the UK for PPI Science

The number of industry and research grant supported research positions, as declared from survey data, is 117 in a roughly 2:1 split PhD students to Research assistants. In the last survey of 2013 members of the community were asked to declare their area of works, number of researchers and, at their discretion, how much funding they have received. From this an estimate of the total amount of funding in the UK has been approximated; this equates to approximately £5 million per year. The funding is spread across the key areas fairly evenly with perhaps molecular modelling / chemoinfomatics being the lowest funded compared to molecule synthesis and biological measurements.

Current Community Assessment of the Key Challenges

Eleven key challenges and capabilities rose to the top. The community has marked fairly favourably for progress in the area of Measurement of affinity of modulators, although clearly there is still work to do. The community recognised progress in Protein structure determination, and the Design of potent inhibitors (or gaining potency / affinity). Although slightly more significantly the community thought that Target validation of a PPI, and Understanding or predicting if a PPI can be modulated as key areas to work on. Underpinning all of these is the need to find 'hit-material', a chemical start point to build affinity, co-crystallise or validate a target. This has been captured in the design or supply of fragment or compound libraries. This particular area is a key area for development .

Cell penetration is clearly the major issue in the area. Root cause analysis of this problem points to several factors - lack of sufficient potency can confound the view that cell penetration is the problem. In addition the challenges of in-cell measurement of affinity and / or measurement of permeability in relevant systems impede progress in this area.

Generating tool compounds, libraries and both sets of fragments and their optimisation also remain issues. Again looking at causes of these problems, the classification of PPI types was highlighted as was the desire to estimate their 'druggability'. In most areas of drug hunting the classification and sub-classification of protein target classes has been an intrinsic part of systematising approaches to finding inhibitors.
Exploitation Route Leveraging this support, UK pharma industry, and in particular the biotech industry, will then be well placed having collaborated with principal investigators to invent the new drugs of the future. The most probable areas for breakthroughs are in oncology, inflammation and anti-infectives. These are areas of significant benefit to the aging UK population also facing the emerging challenge of drug-resistant infectious agents. New drugs in these research areas can reach peak year sales of well over one billion dollars per annum representing significant high technology manufacturing income to the UK.The potential impact for the UK economy presents a clear case to continue PPI-Net and to formulate a PPI RoadMap that can be of value to the community The surveys and interviews have shown there is a real possibility that thanks to the internationally unique PPI network, the UK could take a leading global role in this area. This is largely due to the solid base of expert and informed activity both in academia and industry, the potential to reorient further academic expertise in the direction of this sector due to the particularly large number of outstanding and interesting challenges, and the appetite for further collaboration and engagement.. Many of the challenges highlighted by the community concern prediction and computer aided design. In this field the UK has a strength in design and software engineering to create leading tools. The UK has a strong reputation for drug design (medicinal chemistry) and it will be this capability that will crack the issue concerning affinity and the right pharmacokinetic properties. Recent downsizing by several large companies has placed many medicinal chemists into SME and starts-ups, which are well placed to exploit and succeed in PPI drug space.
Sectors Pharmaceuticals and Medical Biotechnology

Description The network has spawned a significant number of new collaborations including between academica and industry. It has also led to a large critical mass award to the research team at leeds and the establishment of a PPI library at Imperial.
First Year Of Impact 2013
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

Description Knowledge Transfer Secondment Award, EPSRC Internal Imperial College Scheme
Amount £46,344 (GBP)
Organisation Imperial College London 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 03/2014
Title PPI network map 
Description Connections through collaborations in the field of PPI research in the UK 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? No  
Description Closing The Loop on Drug Discovery With Adam Nelson 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution At the moment it is purely conceptual, but we have explored how EVV 2DIR spectroscopy could be used as a one stop biophysical method for rapidly determining both binding affinity and geometry of binding for a drug interacting with a protein target. We have also thought through how this will be formatted in high throughput and made a project application to the Rosalind Franklin Institute to turn the idea into reality.
Collaborator Contribution At the moment it is purely conceptual, but we have explored how EVV 2DIR spectroscopy could be used as a one stop biophysical method for rapidly determining both binding affinity and geometry of binding for a drug interacting with a protein target. We have also thought through how this will be formatted in high throughput and made a project application to the Rosalind Franklin Institute to turn the idea into reality.
Impact Project application to the Rosalind Franklin Institute
Start Year 2017