Center for structural molecular biotechnology

Abstract

The Center for Structural Molecular Biotechnology (CBME) is a joint initiative resulting from existing collaborative research projects involving: the (I) Laboratory of Protein Crystallography and Structural Biology of the Institute of Physics of Sao Carlos (IFSC), University of Sao Paulo; (II) the National Synchrotron Light Laboratory (LNLS), Campinas; (III) the Laboratory of Natural Products and Organic Synthesis of the Department of Chemistry, Federal University of Sao Carlos (DQ-UFSCar); (IV) researchers from the Department of Genetics and Evolution (DGE-UFSCar) and Department of Physiological Sciences (DCF-UFSCar). The major goal of this Center is to perform both applied and basic research as well as technological development in all areas of biotechnology that depend on Structure Based Molecular Design, specifically in the rational design of new structure-based compounds (drugs, vaccines, pesticides, herbicides) and in protein engineering. In order to achieve this goal the CBME promotes an integrated multidisciplinary approach including the application of the techniques of Molecular Biology, Biochemistry, Structural Biology (Protein Crystallography, Multidimensional NMR, Spectroscopy, Molecular Modeling and Bioinformatics), Medicinal Chemistry based on both Synthetic and Natural Product Chemistry, Molecular Immunology, Cell Biology and Pharmacology. The projects undertaken by the CBME are selected on the basis of social, industrial and medical demand. Maximum integration and collaboration with the private sector is always sought, particularly with pharmaceutical and biotechnology companies and research institutes within the health and agricultural sectors. The integration of biological sciences with the unique facilities of the LNLS represents a major advantage for the Center. The Brazilian pharmaceutical market is currently worth US$12 billion a year and yet there is no proprietary drug that has ever been developed within the country. The dependence on foreign technology will become critical in sensitive areas such as human health, agriculture and the environment. Areas which are specifically of national interest to Brazil and which are socially highly sensitive as they affect millions of individuals, such as infections tropical diseases for example, run the risk of becoming totally neglected in the research and development priorities of international industry. In direct contrast, Brazil currently possesses one of the richest natural sources of incalculable potential wealth in the form of its biodiversity, up until now the principal source of lead compounds used in drug development. The scope of the activities of the CBME is to contribute to the bridging of this gap, with an integrated research program involving biologists, physicists, chemists, experts in bioinformatics, molecular modeling, pharmacologists, etc…,focused on the elucidation of macromolecular structure and function and its application to the development of useful compounds or newly engineered proteins. Rational Structure Based Drug Design is nowadays the most efficient and cost-effective technology for the development of new drugs, capable of contributing at all stages of the process, from the discovery of new lead compounds, their optimization (in terms of affinity, specificity, efficacy, side-effects) and their approval by the relevant bodies. It is a methodology that is based on the inhibition or stimulation of the biological activity of macromolecules, proteins or nucleic acids (DNA and RNA), responsible for different diseases. The three-dimensional structural information on target molecules permits the discovery and synthesis of complementary compounds which may become potent drugs specifically directed at the targeted disease. Without exception, all of the largest international pharmaceutical companies nowadays include research and development divisions which employ such technology. Recently developed drugs such as the HIV protease inhibitors are a clear example of the power of this technology. This is an intrinsically interdisciplinary science. Once the target disease, parasite or molecular genetics factor responsible has been selected, an integrated effort involving different specialized researchers is required for the discovery of a new drug: Molecular Biology (cloning and expression of the recombinant target proteins); Biochemistry (purification and characterization of the targets); Crystallography (crystallization, synchrotron data collection, structure determination); NMR (high resolution solution studies); Spectroscopic techniques (EPR, CD, fluorescence, FTIR); Drug design (docking, de novo design, theoretical calculations); Medicinal Chemistry (synthesis of designed compounds, search for leads in natural products); Pharmacology (in vitro and in vivo biological assays of potential compounds, activity and toxicity tests, optimal doses, efficacy, side-effects, etc...). The above process is not necessarily linear; frequently it is necessary that many stages are repeated in a cyclical fashion. However, the possibility to visualize accurately the target site of the drug and of complexes of intermediate compounds can lead rapidly to the convergence of the drug design process, with all the advantages previously mentioned: speed, low relative cost, greater specific activity and as a consequence a reduction in side-effects. Similarly, in the international context, the modern biological sciences have become characterized by the interdisciplinary nature of the theoretical and experimental approaches employed. In all of the large research groups of the world one can readily recognize the total integration between specific researches areas involved in Structural Biology. In Brazil, one can still see a marked segregation among these areas, with the sporadic collaboration that exists limited by the very structure of the university departments. The establishment of an inter-institutional research nucleus, dedicated to Structural Molecular Biotechnology, unique within the country and even within Latin America, which could count on the participation of researchers from different institutions, centre on common projects chosen on the basis, of demand, including a strong interaction and partnership with the production sector, would be the greatest benefit of the centre. With the implementation of a patent law for pharmaceutical and biotechnological products in Brazil, in effect since May/1997, strong interest from the industry in establishing collaborative research projects centered on the development of new compounds is emerging. One example is a research project currently being undertaken by the IFSC group in conjunction with and financed by the company Eurofarma Laboratorios Ltda (2nd in the national ranking), entitled ‘Definition of strategies for research and development of new drugs in Brazil’. What is already clear in this study is that the academic community has to take the initiative in establishing the connection university-industry, with an active role in the prospection of realistic projects for industrial investment. Therefore, the CBME plans to select its projects based on demand and actively pursue integration with industry. The final goal is always the complete transfer of the technology developed to the industrial sector, while naturally respecting intellectual property rights and community ownership of natural products when applicable. On the educational front, the Center will benefit from the strong training programs for students and researchers in the area of Structural Biology, including undergraduate and graduate research training, in all institutions involved. Furthermore, the Center will closely work with the Center for Scientific and Cultural Diffusion, the arm of the university in Sao Carlos for interaction with the community, through strong programs directed towards high school students, further education of school teachers, the extension of libraries of experiments for school demonstrations, education at a distance via the Internet, videos, science fairs, lectures etc. The LNLS has also several activities devoted to the community, including courses, lectures, guided visits and summer schools. This will all contribute to a better understanding of the importance of molecular biology, genetic engineering and biotechnology, key scientific areas for the next century. The research groups involved have demonstrated their capacity for collaborative research in the field, with publications, PhD and MSc theses, and above all state of the art facilities which represent the core of the center. The LNLS represents a US$ 50 million counterpart investment; the IFSC/USP has had an investment of about US$ 3 million in its facilities over the past 8 years; the groups from UFSCar have well established laboratories. The LNLS has approved the construction of a new building to accommodate the whole of their biological research program. The IFSC group has over 1500 m2 of continuous lab. space, including a new area of about 500 m2 allocated for expansion within the next 6 months which will accommodate much of the new equipment envisaged. The salary of staff researchers and technicians, administrative support and general infrastructure is also considerable.