Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Design of a compound that stabilizes the main natural suppressor of tumours

15.10.2008
An interdisciplinary team of researchers, headed by Ernest Giralt at the Institute for Research in Biomedicine (IRB Barcelona) and Javier de Mendoza at the “Institut Català d’Investigació Química” (ICIQ, Tarragona), have discovered a substance with the capacity to maintain protein p53 stable even when it presents certain mutations that promote the appearance of cancer.

Giralt, head of the Chemistry and Molecular Pharmacology programme and senior professor at the University of Barcelona, explains that, “tentatively, this could be the starting point to develop a new approach for anti-tumour treatments”. The study has been published today in the journal Proceedings of the National Academy of Sciences (PNAS) in an advanced edition.

Protein p53 is considered the most important tumour suppressor and it is at the centre of the machinery that regulates cell cycle arrest and the death of cells with damaged DNA. In its active form, p53 protein is a tetramer, that is to say it is formed by four identical copies of proteins bound together, which has four domains with differentiated functions: activation of transcription, DNA binding, tetramerization and regulation. The tetramerization domain is responsible for stabilizing the tetrameric structure.

More than 50% of cancer patients have mutations in the p53 gene. Although most of these are located in the DNA binding domain, several mutations are found in the tetramerization domain, thereby causing destabilization of the entire protein with the consequent loss of activity. Two well documented examples of this kind of congenital predisposition are pediatric adrenocortical carcinoma and Li-Fraumeni syndrome. Therefore, the design of compounds with the capacity to stabilize the tetramerization domain of p53 represents a new and attractive strategy for the development of anti-tumour drugs.

The article describes the design, synthesis and study of a compound with the capacity to interact with the p53 tetramerization domain. Javier de Mendoza, group leader at ICIQ and senior professor at the “Universidad Autónoma de Madrid”, explains, “it is a conical shaped molecule with four positive charges prepared to recognize and stabilize four negative charges of the protein”. To obtain results in the design and study of new molecules, it is necessary to have an in-depth knowledge of the language that proteins use to communicate with each other, to recognise each other and to bind to exert their function. From this perspective, more associated with basic science, Giralt emphasizes that “the study demonstrates the high level of maturity” that has been reached in the field of molecular recognition.

Drugs that act as tethers
The first author of the article, Susana Gordo, researcher with Giralt’s team, explains that “this work also opens up a new avenue for the design of drugs based on the use of small molecules that act as moulds or tethers to preserve the active form of proteins”. Among these possible applications of synthetic binding compounds, the researchers point out the stabilization of native forms of proteins or the recovery and rescue of mutated proteins. “The anti-tumoural factor p53, because of its fundamental role in the appearance of cancer, provides a magnificent opportunity for this kind of study”, concludes Giralt.

Through the combination of several techniques, including nuclear magnetic resonance, the researchers have been able to describe in detail the interaction of the new compound with the tetramerization domain. Furthermore, computer simulations and in vitro experiments have allowed the scientists to demonstrate the functionality of the complex.

The design and analysis of the compound has also involved the collaboration of the biologist Vera Martos, Javier de Mendoza’s team, and the researcher Margarita Menéndez at the “Consejo Superior de Investigaciones Científicas”. The computational chemistry part of the study was directed by Carles Bó at ICIQ, with the help of Eva Santos, from the same institute.

Sònia Armengou | alfa
Further information:
http://www.irbbarcelona.org

More articles from Interdisciplinary Research:

nachricht New approach: Researchers succeed in directly labelling and detecting an important RNA modification
30.04.2018 | Westfälische Wilhelms-Universität Münster

nachricht Start of work for the world's largest electric truck
20.04.2018 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt

All articles from Interdisciplinary Research >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>