Directed Molecular Recognition through Next-Generation Hybrid Molecular Imprinting
Lead Research Organisation:
De Montfort University
Department Name: School of Pharmacy
Abstract
The increasing demand for highly effective molecular recognition for sensing and separations has led researchers to search for synthetic substitutes for enzymes and antibodies with emphasis on materials with potential to outperform their biological counterparts in terms of cost, performance, stability and flexibility.
Molecularly Imprinted Polymers (MIPs) are elegant biomimetics that incorporate binding sites bearing steric and chemical functionality complementary to a given target. They represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors and have uses in separation sciences, purification, sensors and catalysis.
In "classical" molecular imprinting, small functional monomers are used to create the binding sites. While this method has proven generally effective, a relatively high level of heterogeneity in rebinding is still observed which lowers the average binding constant and leads to much-reduced selectivity. This "Achilles Heel" has prevented MIPs from fulfilling their potential, and has led to only their limited application in niche areas. A solution to the heterogeneity problem would unleash the transformational potential of MIPs within the multi-billion-dollar diagnostic and analytical markets.
This heterogeneity arises because of the nature of the imprinting process, where functionality is introduced to the target in a random fashion, leaving no scope for the correction of errors that arise during the subsequent formation of the binding pocket in the polymeric matrix. We will address these issues by developing a novel two-step process towards the formation of imprinted polymeric nanoparticles of exceptionally high affinity and selectivity.
It will exploit a method developed by Fulton that introduces error-correction into the templating process, and a separate method developed by Turner to then fix the binding site within a rigid polymeric nanoparticle "scaffold". This hybridisation will deliver optimized binding sites "locked" into a more rigid structure - creating new synthetic biomimetics with reduced heterogeneity, while incorporating biocompatibility through component selection. These hybrid MIPs can truly challenge and replace their biological counterparts - creating significant impact in the field of molecular recognition and smart materials.
Two targets have been selected to drive the development of these chemistries. These differ in size and application: a protein and a bioactive (antibiotic) drug, but both targets have significant commercial potential, in clinical and environmental settings. Monitoring of antibiotics is key for understanding required effective dosage, but also for studying leakage into the environment from illegal use or overuse, which leads to numerous other serious issues such as bacterial resistance. The protein target offers a demonstration of the MIP nanoparticle ability to disrupt ligand-receptor binding, where the MIP itself can act with inhibitory "drug-like" properties. Through these models we aim to demonstrate the validity and potential of the proposed novel MIP systems.
The project will use facilities at De Montfort University and Newcastle University to develop the new approach. With an experienced project team this interdisciplinary proposal, which covers organic, polymer and analytical chemistry, will take a new approach to MIP synthesis, building on existing proof-of-concept ideas, and develop them further, translating the novel synthetic processes described here into viable options for artificial molecular recognition which can be exploited in several ways. Here we will develop the synthetic methods to be scalable through clear step processes, with automation in mind.
MIP Diagnostics are a UK company based in Bedford who will support the project by their detailed knowledge of MIP design, implementation, and application, with sight towards commercialisation of the technology.
Molecularly Imprinted Polymers (MIPs) are elegant biomimetics that incorporate binding sites bearing steric and chemical functionality complementary to a given target. They represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors and have uses in separation sciences, purification, sensors and catalysis.
In "classical" molecular imprinting, small functional monomers are used to create the binding sites. While this method has proven generally effective, a relatively high level of heterogeneity in rebinding is still observed which lowers the average binding constant and leads to much-reduced selectivity. This "Achilles Heel" has prevented MIPs from fulfilling their potential, and has led to only their limited application in niche areas. A solution to the heterogeneity problem would unleash the transformational potential of MIPs within the multi-billion-dollar diagnostic and analytical markets.
This heterogeneity arises because of the nature of the imprinting process, where functionality is introduced to the target in a random fashion, leaving no scope for the correction of errors that arise during the subsequent formation of the binding pocket in the polymeric matrix. We will address these issues by developing a novel two-step process towards the formation of imprinted polymeric nanoparticles of exceptionally high affinity and selectivity.
It will exploit a method developed by Fulton that introduces error-correction into the templating process, and a separate method developed by Turner to then fix the binding site within a rigid polymeric nanoparticle "scaffold". This hybridisation will deliver optimized binding sites "locked" into a more rigid structure - creating new synthetic biomimetics with reduced heterogeneity, while incorporating biocompatibility through component selection. These hybrid MIPs can truly challenge and replace their biological counterparts - creating significant impact in the field of molecular recognition and smart materials.
Two targets have been selected to drive the development of these chemistries. These differ in size and application: a protein and a bioactive (antibiotic) drug, but both targets have significant commercial potential, in clinical and environmental settings. Monitoring of antibiotics is key for understanding required effective dosage, but also for studying leakage into the environment from illegal use or overuse, which leads to numerous other serious issues such as bacterial resistance. The protein target offers a demonstration of the MIP nanoparticle ability to disrupt ligand-receptor binding, where the MIP itself can act with inhibitory "drug-like" properties. Through these models we aim to demonstrate the validity and potential of the proposed novel MIP systems.
The project will use facilities at De Montfort University and Newcastle University to develop the new approach. With an experienced project team this interdisciplinary proposal, which covers organic, polymer and analytical chemistry, will take a new approach to MIP synthesis, building on existing proof-of-concept ideas, and develop them further, translating the novel synthetic processes described here into viable options for artificial molecular recognition which can be exploited in several ways. Here we will develop the synthetic methods to be scalable through clear step processes, with automation in mind.
MIP Diagnostics are a UK company based in Bedford who will support the project by their detailed knowledge of MIP design, implementation, and application, with sight towards commercialisation of the technology.
Organisations
- De Montfort University (Lead Research Organisation)
- Aptamer Group (Collaboration)
- University College London (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- MIP Diagnostics (Collaboration)
- Newcastle University (Collaboration)
- UNIVERSITY OF BRIGHTON (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- UNIVERSITY OF STRATHCLYDE (Collaboration)
- UNIVERSITY OF SOUTHAMPTON (Collaboration)
- MIP Diagnostics Limited (Project Partner)
People |
ORCID iD |
Nicholas Turner (Principal Investigator) |
Publications
Piletsky SA
(2022)
Modulation of acetylcholinesterase activity using molecularly imprinted polymer nanoparticles.
in Journal of materials chemistry. B
Sullivan MV
(2022)
A molecularly imprinted polymer nanoparticle-based surface plasmon resonance sensor platform for antibiotic detection in river water and milk.
in Analytical and bioanalytical chemistry
Sullivan MV
(2023)
Highly Selective Aptamer-Molecularly Imprinted Polymer Hybrids for Recognition of SARS-CoV-2 Spike Protein Variants.
in Global challenges (Hoboken, NJ)
Description | New Synthetic Chaperones to Enhance Protein Activity |
Amount | £1,301,462 (GBP) |
Funding ID | EP/V056085/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2022 |
End | 12/2023 |
Description | Academic LInk with University of Birmingham |
Organisation | University of Birmingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Working with Prof James Tucker and Prof Paula Mendes Engagement with DNA synthesis for this proposal. Open discussions. Provision of target sequences and materaisl for DNA synthesis |
Collaborator Contribution | They have provided with synthetic aptamers under our guidance and continue to do so, using instrumentation they have. |
Impact | 3 paper accepted. A 4th is under review new joint grant applciation in process (mendes) |
Start Year | 2020 |
Description | Academic link with University of Strathclyde |
Organisation | University of Strathclyde |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | New Activity (collaboration with Prof Damion Corrigan) |
Collaborator Contribution | They have been testing our aptaMIPs for performance on new sensor platform and for biological activity. We have passed aptaMIPs materials across which are been tested for activity via an electrochemical method. |
Impact | Preliminary data for grant submission achieved. Proposal prepared and sent to EPSRC |
Start Year | 2020 |
Description | Aptamer Group |
Organisation | Aptamer Group |
Country | United Kingdom |
Sector | Private |
PI Contribution | From the grant linked this has led to a new partnership in progress with The Aptamer group (York) for support of grant submission. This grant has provided an active collaboration and we are moving forward with discussions on further applications. We are working on development of hybrid materials using materials from the company. Several publications are in draft where we are improving aptamers through this method. A formal NDA/MTA is in place Aptamer group have supported with in-kind support a fellowship bid (EPSRC Dec 2020) |
Collaborator Contribution | AG are providing sequences for specific targets that we are using for basing the research on. Support for successful EPSRC Fellowship bid. (Dec 2020). engaging in patent discussions and applications of developed materials. Papers published with Aptamer Group as collaborative team |
Impact | https://pubs.rsc.org/en/content/articlelanding/2021/py/d1py00607j 2 further publications are in submission |
Start Year | 2015 |
Description | Collaboration with Baker - Southampton Chemistry |
Organisation | University of Southampton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are exploring synthetic methods to make new phosphonamidites. My team are leading on this synthetically |
Collaborator Contribution | Yssy Baker is providing knowhow |
Impact | New compounds for application into polymer synthesis |
Start Year | 2022 |
Description | Collaborative Partnership - MIP Discovery |
Organisation | MIP Diagnostics |
Country | United Kingdom |
Sector | Private |
PI Contribution | Formal collaborative agreement signed with MIP Discovery. Licence options and input to research Agreement covers publication and dissemination of joint research |
Collaborator Contribution | Support knowhow/ facilities on grants. Joint projects. |
Impact | Joint research currently being undertaken |
Start Year | 2022 |
Description | Nanoparticles |
Organisation | University of Leicester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I have strong links with the research group of Professor Piletsky, prior of Cranfield, but now Leicester Chemistry. We have regular research meetings to discuss current projects and future ideas. We also share equipment and methods. |
Collaborator Contribution | Discussions on nanoparticle production and use of specialized equipment based at Leicester. Support on successful EPSRC submission (letter of support as project partner) Joint submission of papers. Joint submission of grants (CRUK - EPSRC) |
Impact | Several papers as found in Publications. Latest of which was published in 2022 Grant submissions |
Description | Research Collaboration - Bhavik Patel |
Organisation | University of Brighton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preparation of materials for electrochemical detection of disease states (biomarkers). Submission of two proposals (awaiting results) Joint supervision of PhD student - linked to grants Research leading to manuscript submission |
Collaborator Contribution | Submission of two proposals (awaiting results) Joint supervision of PhD student - linked to grants Electrochemical experiment leading to publication submission |
Impact | One submission of manuscript (under review) 2 joint proposals |
Start Year | 2021 |
Description | Research Collaboration with Booth, UCL |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Based on my expertise from the following two grants and my move to Uni of Sheffield, i was part of the team who led a CDT submission. This partnership was joint across three universities. Engaged with stakeholders, prepared writing . From this a new collaboration with Mike Booth (UCL Chemistry) has started |
Collaborator Contribution | Booth brings novel modification chemistry to enable aptamip preparation |
Impact | CDT submission. New research collaboration |
Start Year | 2022 |
Description | Sensor Collaboration - Peeters |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration with Dr Marloes Peeters (Chen Eng - Newcastle University) on sensor design. We have provided access to instrumentation and knowhow for polymer development |
Collaborator Contribution | Two projects have been focus of the interaction. Both targeting protein templates. We have provided material performance analysis using EPSRC supported instrumentation. Data provided has gone into two manuscripts |
Impact | 2 Paper manuscript in submission process. Expected in 2023 |
Start Year | 2020 |
Description | Interview by Guardian Newspaper |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviewed for article on Aptamer technology - supporting Apatmer Group profile article in the guardian |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.theguardian.com/business/2022/dec/25/aptamer-york-biotech-cancer-treatments |
Description | Invited Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Invited Talk to present research at: University of Sheffield This led to being approached by University for Job Offer |
Year(s) Of Engagement Activity | 2022 |