Novel analgesics based on antagonism of TRPV1-AKAP79 binding
Lead Research Organisation:
University of Cambridge
Department Name: Biochemistry
Abstract
Pain is a significant clinical problem, because all existing analgesics have major side effects and are also poorly effective in many clinically important types of pain. A membrane ion channel, TRPV1, which is activated by heat, is critical for pain because when tissues are damaged, inflammatory mediators lower the temperature threshold of TRPV1 so that it can be activated even by normal body heat and thus cause ongoing pain. We have discovered how to prevent the effects of inflammatory mediators on TRPV1. A scaffolding protein, AKAP79, forms a "basket" structure which holds close to TRPV1the enzymes responsible for lowering its threshold. We have identified the binding site and can prevent binding using competitor peptides. These peptides give good analgesia in a mouse models of pain, including in a model of diabetic neuropathy, an intractable human pain condition. We will develop improved TRPV1-AKAP79 blocking peptides as better analgesics for intractable forms of pain.
Publications
Brear P
(2020)
Proposed allosteric inhibitors bind to the ATP site of CK2a
Cartmell A
(2018)
A surface endogalactanase in Bacteroides thetaiotaomicron confers keystone status for arabinogalactan degradation
in Nature Microbiology
Cartmell A
(2019)
Author Correction: A surface endogalactanase in Bacteroides thetaiotaomicron confers keystone status for arabinogalactan degradation.
in Nature microbiology
Grantham NJ
(2017)
An even pattern of xylan substitution is critical for interaction with cellulose in plant cell walls.
in Nature plants
Jalan AA
(2020)
Chain alignment of collagen I deciphered using computationally designed heterotrimers.
in Nature chemical biology
| Description | TRPV1 is a target for new analgesics to tackle the largely unmet need in neuropathic pain conditions. However, direct attempts to knock out its function have been hampered by two major side effects: blocking TRPV1 impairs heat sensation (which could lead to accidental burns), and elevates body temperature (which could be fatal). These two drawbacks have largely halted efforts to develop direct blockers of TRPV1, despite the the potential market (estimated at $4bn). We have focused instead on interfering with the larger assembly of proteins associated with the activation and inactivation of TRPV1 - the 'TRPV1 signalosome' - that is scaffolded by another protein, AKAP79. Significant new knowledge generated: we have established key structural details regarding the TRPV1 signalosome, and from these, new indirect ways of antagonising TRPV1 activation that are very promising targets for new analgesic drugs. New or improved research methods or skills developed: we have developed methods for producing members of the signalosome recombinantly, new in-vitro assays, and a new cell-based assay that is potentially suitable for porting to a high-throughput format for further drug development. Significant negative results and/or research paths closed off: we have established that TRPV1 requires expression in e.g. HEK293 cells to be reliably active. Important new research questions opened up: (1) we have established previously unknown interactions in the TRPV1 signalosome that are potentially novel drug targets. Particularly noteworthy new research collaborations/partnerships: we have engaged with LifeArc as a potential means of taking our cell-based assay forwards to generate lead molecules for further drug development. (2) we have embarked on addressing a new related basic research question regarding how the disordered scaffolding protein assembles the TRPV1 signalosome. Increased research capability generated from training delivered in specialist skills: research staff employed on the grant have acquired many important skills in protein production, structural studies, and assay development in multiple formats. |
| Exploitation Route | We have established novel ways of targeting TRPV1 for the alleviation of neuropathic pain, that will be exploited initially by us and LifeArc, but could be taken forwards by others once published. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Novel analgesics based on antagonism of the TRPV1 kinase scaffold |
| Amount | £29,915 (GBP) |
| Funding ID | RG96069 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2020 |
| End | 08/2020 |
| Title | Suite of in vitro biophysical experiments for the study of multivalent (allovalent) interactions. |
| Description | We establish a novel combination of in vitro biophysical experiments and NMR spectroscopy that reveal previously hidden binding sites in disordered scaffold proteins. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | Early days, but we envisage widespread applicability and usage. It will also open up the creation of new theoretical binding models for such systems. |
| Description | Development of a high-throughput platform for the discovery of new analgesic drug leads. |
| Organisation | LifeArc |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | We have secured funding which will enable us to develop a robust platform that is suitable for high-throughput screening of potential small-molecule drugs by LifeArc. |
| Collaborator Contribution | LifeArc have supported our application and - if we are successful - will take the screening programme forwards to generate a list of lead molecules at the end of the funding period. |
| Impact | We have secured pump-prime funding through the BBSRC Impact Acceleration Account through this collaboration, which will support our assay development efforts. |
| Start Year | 2019 |
| Description | Invited international talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | I gave an invited talk on the Zoom platform for "IDP seminars", a biweekly virtual (and highly international) seminar on intrinsically disordered proteins, run by Magnus Kjaergaard and Alex Holehouse. The series was to connect researchers who otherwise could no longer interact due to the pandemic. URL: http://idpseminars.com//talks/2021-04-29-talk (for some reason this is rejected as invalid below) |
| Year(s) Of Engagement Activity | 2021 |