Project acronym AZIDRUGS
Project Molecular tattooing: azidated compounds pave the path towards light-activated covalent inhibitors for drug development
Researcher (PI) András MÁLNÁSI-CSIZMADIA
Host Institution (HI) DRUGMOTIF KORLATOLT FELELOSSEGU TARSASAG
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary Until now the greatest limitation in the application of bioactive compounds has been the inability of confining them specifically to single cells or subcellular components within the organism. Our recently synthesized photoactive forms of bioactive compounds solve this problem. We have developed effective chemical synthesis methods to attach an azide group to small drug-like molecules, which makes them photoactive. As a result, light irradiation can induce the covalent attachment of these molecules to their target enzymes. By controlling the timing and position of light irradiation it is possible to confine the effect of these molecules in time and space. It is important to emphasize that azidation is the smallest possible modification (adding 3 nitrogen atoms) that makes a compound photoactive and based on our experience it does not alter biological activities of most of the original compounds.
Azidated inhibitors give unprecedented freedom to researchers because the covalent compound-target formations allow them to address questions which could not have been addressed before. Three major advantages are obtained by using azidated compounds 1: determination of small molecule interactome becomes highly effective, especially, the weak interactions can be determined, which was not possible before 2: it improves the pharmacodynamic and pharmacokinetic properties of biological compounds as the covalent attachment prolongs their effect. 3: Recently, we showed that photoactivation can be initiated by two-photon excitation, thereby confining the effect to femtoliter volumes and well-controlled spatial locations. This feature provides unprecedented spatial and temporal control in localizing the effect of biological compounds in cellular and subcelluler level in in vivo experiments. By realizing the need for photoactive compounds, the PI has established Drugmotif Ltd., a spin-off company, which provides the customers with special azidated chemicals for high-tech research.
Summary
Until now the greatest limitation in the application of bioactive compounds has been the inability of confining them specifically to single cells or subcellular components within the organism. Our recently synthesized photoactive forms of bioactive compounds solve this problem. We have developed effective chemical synthesis methods to attach an azide group to small drug-like molecules, which makes them photoactive. As a result, light irradiation can induce the covalent attachment of these molecules to their target enzymes. By controlling the timing and position of light irradiation it is possible to confine the effect of these molecules in time and space. It is important to emphasize that azidation is the smallest possible modification (adding 3 nitrogen atoms) that makes a compound photoactive and based on our experience it does not alter biological activities of most of the original compounds.
Azidated inhibitors give unprecedented freedom to researchers because the covalent compound-target formations allow them to address questions which could not have been addressed before. Three major advantages are obtained by using azidated compounds 1: determination of small molecule interactome becomes highly effective, especially, the weak interactions can be determined, which was not possible before 2: it improves the pharmacodynamic and pharmacokinetic properties of biological compounds as the covalent attachment prolongs their effect. 3: Recently, we showed that photoactivation can be initiated by two-photon excitation, thereby confining the effect to femtoliter volumes and well-controlled spatial locations. This feature provides unprecedented spatial and temporal control in localizing the effect of biological compounds in cellular and subcelluler level in in vivo experiments. By realizing the need for photoactive compounds, the PI has established Drugmotif Ltd., a spin-off company, which provides the customers with special azidated chemicals for high-tech research.
Max ERC Funding
150 000 €
Duration
Start date: 2013-12-01, End date: 2014-11-30
Project acronym COLIBRI
Project Novel platform for combinatorial genetic libraries by recombination
Researcher (PI) Michael LISBY
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary Assembly of combinatorial genetic libraries for identification of biomolecules with novel or improved properties requires high fidelity and efficiency to produce the greatest spectrum of genetically diverse clones. We have been developing homologous recombination (HR) as a platform for the production of combinatorial genetic libraries for affinity maturation and diversification of human therapeutic antibodies. Therapeutic antibodies have a great clinical potential in various therapeutic settings including the treatment of a number of oncology, autoimmune and infectious diseases, organ transplantation, and others. In brief, we describe a method, where CDR-encoding DNA oligos and a gapped vector containing the heavy and light chain genes are cotransformed into budding yeast Saccharomyces cerevisiae for in vivo assembly by HR. Importantly, the affinity of resulting antibody clones in the generated library can be directly assayed by yeast surface display without subcloning and retransformation. Furthermore, mating two haploid yeast strain libraries each encoding a variation of heavy chain or light chain genes enables fast screening of the heavy/light chain combinations displayed by the resulting diploids. Finally, this method can be generalized to generate combinatorial genetic libraries for other applications.
Summary
Assembly of combinatorial genetic libraries for identification of biomolecules with novel or improved properties requires high fidelity and efficiency to produce the greatest spectrum of genetically diverse clones. We have been developing homologous recombination (HR) as a platform for the production of combinatorial genetic libraries for affinity maturation and diversification of human therapeutic antibodies. Therapeutic antibodies have a great clinical potential in various therapeutic settings including the treatment of a number of oncology, autoimmune and infectious diseases, organ transplantation, and others. In brief, we describe a method, where CDR-encoding DNA oligos and a gapped vector containing the heavy and light chain genes are cotransformed into budding yeast Saccharomyces cerevisiae for in vivo assembly by HR. Importantly, the affinity of resulting antibody clones in the generated library can be directly assayed by yeast surface display without subcloning and retransformation. Furthermore, mating two haploid yeast strain libraries each encoding a variation of heavy chain or light chain genes enables fast screening of the heavy/light chain combinations displayed by the resulting diploids. Finally, this method can be generalized to generate combinatorial genetic libraries for other applications.
Max ERC Funding
150 000 €
Duration
Start date: 2014-05-01, End date: 2015-04-30
Project acronym KNOTOUGH
Project KNOTOUGH: Super-tough knotted fibers
Researcher (PI) Nicola PUGNO
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TRENTO
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary "This project is intended to lead to the identification, design and development of a novel, economically viable pre-industrial process, to make the world's toughest synthetic fibres. Our new concept to obtain fibers with unconventional toughness is indeed very simple and robust: the introduction in high-strength fibers of a smart frictional element, in the form of a large slip loop in a slider, that in its simplest configuration is a knot. A preliminary proof of concept implementation has already been performed, realizing the highest toughness value for a fiber to date, using commercial Zylon® and reaching 1400 J/g, surpassing for the first time 1000 J/g. This knot-based manufacturing strategy is already a milestone of the ERC Starting Grant ""Bio-inspired Hierarchical Super Nanomaterials"" (BIHSNAM), and it has proven to be an extremely simple yet efficient way for the production of ultra-tough materials. Instead of pursuing the synthesis of new materials, we fully exploit the potential of already existing ones, with an evident improvement in the potential quality of current industrial production, exploiting a relatively uncomplicated and economical, and therefore industrially attractive method. The aim of KNOTOUGH is therefore to optimize (identifying the proper slider element, e.g. knot topology, for maximizing toughness), consolidate and develop this manufacturing procedure, taking it to a pre-commercial stage, with potential applications in all those industrial manufacturing sectors where energy absorption is important (e.g., sporting goods, automotive, aerospace, protective devices)."
Summary
"This project is intended to lead to the identification, design and development of a novel, economically viable pre-industrial process, to make the world's toughest synthetic fibres. Our new concept to obtain fibers with unconventional toughness is indeed very simple and robust: the introduction in high-strength fibers of a smart frictional element, in the form of a large slip loop in a slider, that in its simplest configuration is a knot. A preliminary proof of concept implementation has already been performed, realizing the highest toughness value for a fiber to date, using commercial Zylon® and reaching 1400 J/g, surpassing for the first time 1000 J/g. This knot-based manufacturing strategy is already a milestone of the ERC Starting Grant ""Bio-inspired Hierarchical Super Nanomaterials"" (BIHSNAM), and it has proven to be an extremely simple yet efficient way for the production of ultra-tough materials. Instead of pursuing the synthesis of new materials, we fully exploit the potential of already existing ones, with an evident improvement in the potential quality of current industrial production, exploiting a relatively uncomplicated and economical, and therefore industrially attractive method. The aim of KNOTOUGH is therefore to optimize (identifying the proper slider element, e.g. knot topology, for maximizing toughness), consolidate and develop this manufacturing procedure, taking it to a pre-commercial stage, with potential applications in all those industrial manufacturing sectors where energy absorption is important (e.g., sporting goods, automotive, aerospace, protective devices)."
Max ERC Funding
149 490 €
Duration
Start date: 2015-03-01, End date: 2016-02-29
Project acronym NANOTHERAPY
Project A Novel Nanocontainer drug carrier for targeted treatment of cancer
Researcher (PI) George KORDAS
Host Institution (HI) "NATIONAL CENTER FOR SCIENTIFIC RESEARCH ""DEMOKRITOS"""
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary The clinical use and effect of most conventional therapies (e.g. for cancer) are limited, either due to insufficient accumulation of the drug in the target tissue or its severe toxic effects on healthy tissues. Consequently, many treatments are not achieving their full effect and many other highly promising compounds never make it to the market. A promising approach to address this issue of bioavailability is the design and development of nanocarriers. These nanocarriers need to provide stable protection of the compound in the blood stream while they should release the compound at the targeted tissue. Currently, there are no nanocarriers available that effectively address this challenging trade-off.
We have constructed nanocontainers (NCs) that show high promise to address this issue. Our NCs are engineered from biocompatible and biodegradable polymers and are unique in their stability and resistance to drug leakage in the circulation, while they exert conformational changes under specific conditions targeting at the pathological tissue, inducing localised drug release. This technology leverages the fact that tumours (as well as other types of diseased tissue) are known to have specific extracellular environments with lower pH, higher temperature and enhanced glutathione levels compared to healthy tissues. Our NCs integrate four stimuli, namely pH, temperature (T), reducing environments (glutathione) and alternating magnetic fields. With the PoC grant we aim at obtaining in vivo evidence of the functional added value of our proprietary NCs for the delivery of anti-tumour and antibacterial drugs. Furthermore, we aim to strengthen our IP position and develop a business plan thatdescribes theoptimal route-to-market for our technology.
Summary
The clinical use and effect of most conventional therapies (e.g. for cancer) are limited, either due to insufficient accumulation of the drug in the target tissue or its severe toxic effects on healthy tissues. Consequently, many treatments are not achieving their full effect and many other highly promising compounds never make it to the market. A promising approach to address this issue of bioavailability is the design and development of nanocarriers. These nanocarriers need to provide stable protection of the compound in the blood stream while they should release the compound at the targeted tissue. Currently, there are no nanocarriers available that effectively address this challenging trade-off.
We have constructed nanocontainers (NCs) that show high promise to address this issue. Our NCs are engineered from biocompatible and biodegradable polymers and are unique in their stability and resistance to drug leakage in the circulation, while they exert conformational changes under specific conditions targeting at the pathological tissue, inducing localised drug release. This technology leverages the fact that tumours (as well as other types of diseased tissue) are known to have specific extracellular environments with lower pH, higher temperature and enhanced glutathione levels compared to healthy tissues. Our NCs integrate four stimuli, namely pH, temperature (T), reducing environments (glutathione) and alternating magnetic fields. With the PoC grant we aim at obtaining in vivo evidence of the functional added value of our proprietary NCs for the delivery of anti-tumour and antibacterial drugs. Furthermore, we aim to strengthen our IP position and develop a business plan thatdescribes theoptimal route-to-market for our technology.
Max ERC Funding
150 000 €
Duration
Start date: 2014-01-01, End date: 2015-05-31
Project acronym REPLICA2
Project REPLICA2: Large-area replication of biological anti-adhesive nanosurfaces
Researcher (PI) Nicola PUGNO
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TRENTO
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary "The project aims at designing and optimizing a pre-industrial process to produce artificial biomimetic anti-adhesive polymer/metal surfaces by direct copy of the morphology of a natural water-repellent substrates such as lotus leaves, and subsequent modification thereof. Thus, morphological modifications are exploited rather than chemical treatments to obtain water/ice/particle-repellent surfaces. The experimental procedure, devised in the ERC Starting Grant ""Bio-inspired Hierarchical Super Nanomaterials"" (BIHSNAM), has proven to be an extremely simple yet efficient way to exploit natural nano- and micro-structural hierarchical designs for the production of durable artificial antiadhesive surfaces. A modification and improvement of this process would lead to a considerable simplification in existing industrial production techniques, with the possibility of creating nanoscale features on large surfaces with a relatively uncomplicated and economical, and therefore industrially attractive method. The process under consideration should in this project be technically verified, improved and taken to a pre-commercial stage, for applications in industrial sectors such as white goods, automotive, air transport, and possibly advanced construction materials."
Summary
"The project aims at designing and optimizing a pre-industrial process to produce artificial biomimetic anti-adhesive polymer/metal surfaces by direct copy of the morphology of a natural water-repellent substrates such as lotus leaves, and subsequent modification thereof. Thus, morphological modifications are exploited rather than chemical treatments to obtain water/ice/particle-repellent surfaces. The experimental procedure, devised in the ERC Starting Grant ""Bio-inspired Hierarchical Super Nanomaterials"" (BIHSNAM), has proven to be an extremely simple yet efficient way to exploit natural nano- and micro-structural hierarchical designs for the production of durable artificial antiadhesive surfaces. A modification and improvement of this process would lead to a considerable simplification in existing industrial production techniques, with the possibility of creating nanoscale features on large surfaces with a relatively uncomplicated and economical, and therefore industrially attractive method. The process under consideration should in this project be technically verified, improved and taken to a pre-commercial stage, for applications in industrial sectors such as white goods, automotive, air transport, and possibly advanced construction materials."
Max ERC Funding
147 000 €
Duration
Start date: 2014-03-01, End date: 2015-02-28
Project acronym ROMANS
Project Rotating Opto-Magnetic Analysis System
Researcher (PI) Anja BOISEN
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Proof of Concept (PoC), PC1, ERC-2013-PoC
Summary The purpose of this PoC project is to develop a prototype of portable, highly sensitive and low cost technology for point-of care detection of inflammatory diseases biomarkers. At DTU Nanotech we have developed a completely new technology which holds a great potential to become, in a short period, an extremely useful tool for small medical facilities, family doctors, and chronically ill patients. The core readout element is represented, as in the HERMES project, by an optical pickup head, as used in CD, DVD-ROM or BLU-RAY, which embeds in a single optical path both a laser source and a high-resolution photodetector. By measuring how the light is scattered by magnetic nano-particles actuated by an external AC field we have demonstrated that it is possible to detect low concentration of analytes present in the sample. The key feature of our invention is that blood preconcentration and analyte readout are integrated into the same magnetic-based operations, leading to a compact, low-cost and user-friendly device. Doctors will benefit from our technology which allows performing multiple analyses without relying on centralized laboratories. A fast technology capable to detect multiple parameters would for example allow patient screening at the family doctors’ offices, or would allow chronic diseases patients to be monitored without the need of regularly going to the hospital. The scope of the project is both to provide a benchmarked prototype and to identify the best approach to commercialize the invention. The PoC grant will provide the instruments for understanding the low-cost point-of-care market more deeply, in order to start addressing as soon as possible the challenges of breaking through a complex market such as human diagnostics. Thanks to the intrinsic low-cost of the machine components, several cycles of production/testing/evaluation are expected to be performed, facilitating a constant and fast improvement of our platform development and testing.
Summary
The purpose of this PoC project is to develop a prototype of portable, highly sensitive and low cost technology for point-of care detection of inflammatory diseases biomarkers. At DTU Nanotech we have developed a completely new technology which holds a great potential to become, in a short period, an extremely useful tool for small medical facilities, family doctors, and chronically ill patients. The core readout element is represented, as in the HERMES project, by an optical pickup head, as used in CD, DVD-ROM or BLU-RAY, which embeds in a single optical path both a laser source and a high-resolution photodetector. By measuring how the light is scattered by magnetic nano-particles actuated by an external AC field we have demonstrated that it is possible to detect low concentration of analytes present in the sample. The key feature of our invention is that blood preconcentration and analyte readout are integrated into the same magnetic-based operations, leading to a compact, low-cost and user-friendly device. Doctors will benefit from our technology which allows performing multiple analyses without relying on centralized laboratories. A fast technology capable to detect multiple parameters would for example allow patient screening at the family doctors’ offices, or would allow chronic diseases patients to be monitored without the need of regularly going to the hospital. The scope of the project is both to provide a benchmarked prototype and to identify the best approach to commercialize the invention. The PoC grant will provide the instruments for understanding the low-cost point-of-care market more deeply, in order to start addressing as soon as possible the challenges of breaking through a complex market such as human diagnostics. Thanks to the intrinsic low-cost of the machine components, several cycles of production/testing/evaluation are expected to be performed, facilitating a constant and fast improvement of our platform development and testing.
Max ERC Funding
149 833 €
Duration
Start date: 2014-01-01, End date: 2015-03-31
