Project: Integrated Drug Discovery Pipeline for Next Generation Aptamers
Project Goal:_x000D_The goal is to develop an integrated drug discovery pipeline to develop next generation aptamers, the so-called flexmers, based on the integration of the technologies and know-how of the three SME's involved. _x000D__x000D_Background:_x000D_Most drugs that are currently on the market are based on small molecules (< 500 Dalton), which makes them most suitable for cellular uptake. More recently a range of drugs based on monoclonal antibodies has become available that are very specific and have good pharmacokinetic characteristics._x000D_Still both types of drugs have their disadvantages. Small molecule based drugs have limited specificity and poor affinity for their targets and are therefore very limited in modulating protein-protein interactions. Furthermore, a large part of the chemical space for small molecules has already been explored. Monoclonal antibodies (mAbs) are very large molecules that are expensive to produce and not easy to modify and may result in immunogenicity. mAbs also require long development times._x000D__x000D_A third type of drug is formed by aptamers. Aptamers are nucleotide-based single strand oligonucleotides. These structures are capable of binding as a ligand to target molecules, from small molecules to proteins and carbohydrates. Their size sits in between small molecules and antibodies. Aptamers are as specific as antibodies and are less expensive to produce. Still, classic aptamers also have their drawbacks. Their half-life in the body is limited because of degradation and renal clearance. Optimization of the chemical structure of an aptamer towards favorable pharmacokinetic characteristics is associated with two problems. (1) it prolongs the development time of suitable aptamers and, (2), structural changes that prevent degradation might render the aptamer inactive. _x000D__x000D_Next generation aptamers, so-called flexmers, provide an elegant solution for these problems. Flexmers are oligonucleotides based on novel biology and chemistry using non-natural nucleotides. These flexmers have increased half-lives compared to their predecessors, the classic aptamers, based on in-house stability assays based on nuclease activity in Bovine Calf Serum (BCS). Flexmers can readily be used in the selection process against target molecules making the introduction of post-selection modifications obsolete._x000D_Flexmers also have an increased structural diversity through the use of non-natural nucleotides in combination with standard nucleotides that build DNA and RNA. Because the nucleotide backbone is retained, amplification and decoding of the best binders in the flexmer library is still possible. With flexmers the selection and optimization process of aptamers is combined._x000D__x000D_A third issue with aptamers is that their development can also be time-consuming because the standard method to select for aptamers is SELEX (Systematic Evolution of Ligands by Exponential Enrichment), which takes multiple rounds of selection. In the INGA project we speed up this process by introducing two innovations in the selection process._x000D__x000D_The selection itself will be developed and optimized on a platform that directly detects the interaction between the target molecule and the flexmer library, allowing tightly controlled conditions for binding and recovery of flexmers. Decoding of the flexmers that have bound to the target molecule is performed with next generation sequencing, which offers an increase in dynamic range as well as sensitivity of detection. Recent developments in phage display technology have shown that the introduction of NGS can reduce ligand selection from multiple rounds to a single round._x000D__x000D_In conclusion, flexmers will reduce the development time and costs for drug screening and increase the therapeutic potential of next generation aptamers._x000D__x000D_The consortium consists of three Ps, ATDBio, Biaffin and FlexMers._x000D__x000D_ATDBio (UK) has extensive expertise in oligonucleotide synthesis. They are responsible for the synthesis of high quality flexmer libraries, which form the heart of this project. ATDBio also has proprietary chemistry that offers excellent opportunities for alternative oligonucleotide structures. These will be tested in this project as possible flexmers._x000D__x000D_Biaffin (Germany) focuses on SPR technology, which they apply to analyze the interaction between a whole plethora of molecules. Normally SPR is used to measure the interaction between a single target and a single binder. Within this project Biaffin will apply their extensive know-how on SPR to use their platform for the selection of the best flexmers that bind to the target of interest_x000D__x000D_FlexMers BV (The Netherlands, a daughter company of FlexGen Holding BV, see also §3.4.1 ) is specialized in next generation aptamers, that they also named flexmers. FlexMers owns relevant IP to render aptamers more resistant to nuclease degradation as well as to create novel structures. In proof-of-principle experiments FlexMers has shown the feasibility of flexmer selection.
|
Acronym
|
INGA
(Reference Number: 8370)
|
|
Duration
|
01/09/2013 - 29/02/2016
|
|
Project Topic
|
Flexmers are next generation aptamers and provide a novel alternative to drug compounds. To enable a very quick and efficient process for flexmer development, ATDBio, Biaffin and FlexMers BV will combine their expertise to create an integrated drug discovery pipeline for flexmers.
|
|
Network
|
Eurostars
|
|
Call
|
Eurostars Cut-Off 10
|
Project partner
