Nanobiotechnology, high-throughput technologies for life cell and in vivo screening of small molecules for tissue targeting, tumor targeting.
Non viral vectors for gene delivery and expression of foreign gens for gene therapy.
Organic synthesis of natural products. Development of organic methods.
For more details see personal web page: www.wix.com/gerardobyk/nanobiotechnology
1.Nanobiotechnology for drug discovery and diagnostics
2.Total synthesis of natural products
3. combinatorial chemistry and combinatorial screening technologies
4. Non viral gene delivery for gene therapy
Combinatorial Chemistry: Towards the chemistry of the 21st century
In the last twenty years, pharmaceutical companies have invested significant efforts in developing robotics and miniaturization for biological screening purposes. As a result of these efforts, the capacity of biologists to perform in vitro high-throughput screening of chemicals for drug discovery was dramatically improved. The main limitation of this new screening technology lies in the capacity of the chemists to furnish biologists with great diversity and number of products.
Traditionally, drug discovery involved the optimization of lead structures, most likely derived from biological sources, through a multi-step process of serial synthesis and screening. This approach is extremely costly, as each compound will have been individually handcrafted in solution by a synthetic chemist. The need to find more cost-effective methods of drug development, combined with the recent advances in robotic screening which enable the testing of hundreds of thousands of products per year, has led pharmaceutical companies to examine combinatorial synthetic strategies as a means of accelerating drug discovery programs, and increasing the chemical diversity of their compound libraries.
Chemists in academia are aware that novel synthetic tools must be developed in order to meet the increasing requirements of the high-throughput biological screening technology. For this purpose, the use of robotics in organic synthesis may significantly improve the diversity of synthetic libraries, and may allow the finding of new organic reactions. The emerging technology, the so-called ‘Combinatorial Chemistry’, is based on the simple premise that the greater the diversity of compounds tested, the better the chance of finding one that can be developed into a drug or other industrial lead. Although it is theoretically not limited to any specific family of chemical species, the scope of this approach is actually limited as a result of the restrained organic reactions available for synthesis on solid supports, and by the limited quantity of available multi-reagent organic reactions. A main goal of the laboratory of peptidomimetics and genetic chemistry will be to discover and develop new tools for extending the scope of combinatorial chemistry, and the application of these new tools to drug discovery.
The laboratory will focus on the design and delivery of biologically active molecules and complexes for drug research and clinical applications.
Some tasks of the laboratory:
Development of new technologies for automation and miniaturization of organic synthesis: Multicomponent and multistep organic synthesis on solid supports for high throughput synthesis.
Discovery of molecules with interesting biological activity using screening approaches such as combinatorial chemistry and multiple organic synthesis, and rational approaches starting from the natural substrates, especially from peptide sequences.
Definition of the bioactive conformation of biologically active analogs derived from synthetic molecules, or from natural compounds whose pharmacological characteristics are well known.
Development of integrated nanotechnology both for high-throughput organic synthesis and in vivo biological screening.
A new "phage display-like" synthetic system is generated using 2 mm cross-linked mono-dispersed microspheres bearing a panel of fluorescence tags and peptides that are directly synthesized on the microspheres or small molecules covalently conjugated to them. The new system allows screening mixtures of ligands bound to the microspheres using flow-cytometry analysis of the microspheres after incubation with a live cells model PC-3 cell-line in analogy to phage-display peptide method. The advantage of the proposed system is the possibility of screening non natural peptides, combinatorial libraries and small molecules that cannot be expressed and screened using phage display libraries. Two libraries are screened resulting in peptide DUP-1(1-12)2Ala and small molecule Rak-2 both individually synthesized and validated in an independent binding assay. Finally, the cellular fate of DUP-1(1-12)2Ala in PC-3 cell line is demonstrated using confocal laser scanning microscopy.
Figure 1. Design of a phage-like synthetic system and steps of the analysis technique. Background microscopy pictures in steps 2, 3 and 4 are real representations of the steps as seen by inverted microscopy.
Fig. (1). Steps of live cell screening using a phage-like synthetic system.
Development of novel targeted imaging systems for diagnostics in collaboration with French scientists: http://sciencedirect.dogsoso.com/science/article/pii/S0378517311006260
2. Gene therapy
Synthetic DNA delivery agents are of crucial importance for gene therapy as an alternative to viral vectors, since they display potentially less risks in terms of immunogenicity and propagation.
A great deal of work is still needed for obtaining improved gene expression after non-viral gene delivery, especially regarding the in vivo final localization of the DNA complexes. Based on recently published results, the introduction of a targeting moiety into non-viral gene delivery systems promises improved gene expression in the targeted area as result of the accumulation of the complexes.
The laboratory aims to develop non-viral gene delivery systems specifically targeted to tumors. Specific tumor receptors are of particular interest. Thus, targeting ligands addressed to these receptors will allow a selective localization of the therapeutic gene or drug in the tumor area. Coupling of these ligands to complexes carrying suicide genes will promote the specific elimination of tumor cells, resulting in tumor reduction or elimination.
3- Total synthesis of natural compounds with biological activities
Novel methodologies especially employing microwave energy are being developed in the laboratory for the synthesis of biological relevant natural compounds. The lab designs and develop synthetic methodologies for this aim and characterise the obtained molecules for final validation of the natural compounds structure.
Particular research areas (projects):
1. Nano-biotechnology for drug discovery and diagnostics
2. Total synthesis of natural products
3. Combinatorial chemistry and combinatorial screening technologies
4. Non-viral gene delivery for gene therapy
Bachelor or MSc students in chemistry, biophysics, biology, physics, biotechnology, biomedical engineering from any university or recognized college are asked to apply to Prof. Byk for MSc or PhD positions currently open.