In search of new designer drugs

Structural Genome will have US$ 3.5 million to study genes and proteins

The Structural Genome Project, launched this month by FAPESP in partnership with the National Laboratory of Polarized Light (LNLS), linked to the Ministry of Science and Technology, will begin its activities in March of 2001. The Project, which has resources of the order of US$ 3.5 million, will initiate the structural phase of the Genome Projects of FAPESP, with the emphasis being on the Human Genome Cancer Project. It is expected to study the structure of proteins so as to understand their function and the possible development of medicines to combat the various types of cancer.

The first stage of the Structural Genome, with a working period of four years, involves the study of close to 200 expressive genes and their protein. The genes will be selected and given from the various projects of the Genome Program of FAPESP, especially from the Ludwig Institute of Cancer Research, the coordinating center of the Human Genome Cancer Project. The Center of Molecular Structural Biology (CBME/LNLS) will be responsible for the coordination of the work of the Structural Genome.

This center is already clearly active, having resolved structures of close to two dozen proteins by X-ray diffraction analysis. Some of the proteins studied are important targets of inhibitors (with the potential to turn themselves into medicines) for combating sicknesses such as hepatitis B, malaria, variations of Aids typical in Brazil and cancer. The Project will be developed, in the first instance, at close to 15 laboratories of both the public and private sectors in the State of São Paulo. The edital can already be found at the electronic address of FAPESP. Laboratories interested in joining the project should present their proposals/ projects until the 23rd of February of 2001.

Preference will be given to laboratories with experience in the sequencing of DNA and of the cloning of genes. During the first few weeks of March, up to US$ 1.5 million will begin to be liberated among the selected laboratories. Each laboratory will be able to count upon, at the maximum, US$ 100,000 for the development of the research. The values should be applied, in the majority of cases, to the purchase of equipment and reagents, explained the biochemist Dr. Rogério Meneghini, the Director of CBME, who will coordinate the program.

The equipment will be primarily that needed for the expression, purification and crystallization of proteins and the laboratories which already possess them will contribute to lowering the cost of the investment of FAPESP. On the other hand, in a short period of time the CBME will be able to count on a number of spectroscopic pieces of equipment, including nuclear magnetic resonance, to study the structure of the proteins in solution, without the necessity of crystallizing them.

Among the criteria for the selection of the group, one of the main ones is interest in the domination of techniques of purification and crystallization of proteins so that their 3-dimensional structures can come to be unraveled. The knowledge of these structures will be important for the definition of the functions of the proteins in normal cells which will be compared, for example, with cancerous cells. After having de-codified the structure and the functions of the proteins and the way in which they work in determined types of illnesses, the researchers could start on a more advanced phase of this process, the development of inhibitors of their activities (designer drugs), conceived with the purpose of blocking the activities of the proteins which show themselves in an exaggerated form in cancerous cells.

The determination of the 3-dimensional structure of a protein should be achieved by way of the methods of crystallography in sources of polarized light which use the phenomena of the diffraction of x-rays of the molecular crystals of the proteins, and nuclear magnetic resonance (NMR) spectroscopy. This technology demands that the laboratories can count on specialized personnel and that they are equipped with apparatus used in structural molecular biology and related areas, which permits – as well as being able to operate processes of extraction, selection, purification and crystallization – the collection of the data on the protein which is being studied, normally by techniques of NMR or x-rays coming from a polarized light source for example.

A virtual network
In the same manner as the other projects of the FAPESP Genome Project (Xylella Genome, Sugar Cane Genome, Human Cancer Genome and Xanthomonas Genome),the development of the research of the Structural Genome Project will be carried out by way of a virtual network of laboratories under the command of the Center of Structural Molecular Biology, which will place its units of biological research at the disposition of the participants of the program. According to Dr. Meneghini, the Ministry of Science and Technology has determined an allocation of US$ 3.7 million for the budget of 2001 of CBME/LNLS, which will permit that the laboratories of other States can integrate themselves into the network lead by FAPESP.

“It is worth remembering that the idea of the creation of a national network of laboratories of structural molecular biology is in the slipstream of this State program because it is here in São Paulo that close to 60% of the specialized group is concentrated and it was here as well that the Brazilian Genome Project was born and was developed with success.” observed the biochemist Dr. Meneghini. The selected groups will also have the liberty of proposing the study of the proteins in which their own research projects are interested and which have nothing to do with the Genome Projects of FAPESP.

The Scientific Director of FAPESP, Dr. José Fernando Perez, observed that the Structural Genome Project carries a multiple significance because, as well as progressing down the line of the FAPESP Genome Project, which began with the sequencing of the genome of Xylella fastidiosa, it facilitates professional training and unites, for the first time in the country, teams of professionals from various disciplines. Physicists, computer scientists, biochemists and biologists are following only one objective: the production of designer drugs, the new world tendency in science. “Now lets go from the research line to the pharmaceutical line. It is a tremendous challenge, a risky activity, as is everything in science, and we are entering into a very new area at the same time as similar researches are being carried out by the Americans and the Europeans.”

A positive approval
The Structural Genome Project was submitted to the analysis of an international scientific committee at the beginning of the year and approved six months later. “The positive approval of these international assessors represents the confirmation of the success of our Genome Project and shows that, finally, Brazil has begun to be perceived in the exterior as a center of research in molecular biology of excellence, the most sophisticated of Latin America.” said Dr. Perez.

The researches into structural genome in the world are focused on the functional spectrum (or dynamism) of the activities of the Human Genome Project. Firstly came the deciphering and annotations of part of the human genetic code (close to 90%), then the transcription of DNA in RNA (Transscriptomes); and the analysis of the groups of proteins (Proteomes), of fundamental importance for the understanding of the molecular game of the living organisms because it is those who command the spectrum of life.

“The proteins make everything into an organism, thanks to the versatility of their structures: transport the iron to the blood, control the entry of sugar into the cell, make themselves into important hormones and participate in the processes of enormous biological complexity.” explained Dr. Meneghini. He believes that, during this decade, it will be possible to arrive at the first group of products of structural genome – the perfecting of the forms of the diagnosis of cancers, treatments of the most varied types and inhibitors for protein molecules active in diseases of those currently most serious.