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A computational methodology is designed to advance specific drugs against some cancers

VALENCIA, March 9.

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A computational methodology is designed to advance specific drugs against some cancers


A research team from the Department of Biochemistry and Molecular Biology of the Universitat de València (UV), in collaboration with Sarel Fleishman's group, from the Weizmann Institute of Science in Israel, has developed a computer-assisted approach to modulate the intramembrane interactions between proteins.

With this tool, the authors have developed an inhibitor capable of blocking the pro-apoptotic protein BclxL. The work, published in the journal 'PNAS', opens a new avenue for the development of specific drugs against some cancers.

"Our work opens the window to the development of drugs directed against a hitherto unexplored therapeutic target. Not only have we been able to develop an inhibitor of an antiapoptotic protein, but we have also developed the tools for the future development of inhibitors against any process in which involves interactions within biological membranes", Luis Martínez Gil, a researcher at the University of Valencia, points out in a statement.

Cellular apoptosis -they explain from the academic institution- is an essential process in multicellular organisms that contributes to the balance between cell death, proliferation and differentiation, which is relevant for the correct development and functioning of living beings. This makes it necessary for it to be a highly regulated process involving numerous components, including the family of proteins known as Bcl2 (B-cell lymphoma 2).

Interactions between membrane proteins play a central role in apoptosis, but despite their importance, they have not been thoroughly examined due to the difficulty of working with water-soluble proteins. Recent findings suggest that the transmembrane domains (TMDs) of Bcl2 family proteins are also involved in protein-protein interactions at the membrane and that these are crucial to control programmed cell death.

The BclxL transmembrane domain establishes intramembrane interactions with both proapoptotic and antiapoptotic members of the Bcl2 family of proteins. These interactions are key to controlling the action of the protein, that is, protecting it from cell death. Due to its role in the control of apoptosis, BclxL has a predominant role in various forms of cancer and different strategies have been considered to specifically inhibit it.

"To illustrate this approach, we demonstrated that B-cell lymphoma proteins 2 (Bcl2) interact through their TMD to control programmed cell death, or apoptosis. We have next designed sequences that recognize and capture the TMD of an anti-apoptotic member of the Bcl2 family of proteins, which hinders its tumor-inducing properties," says Luis Martínez Gil.

Apart from this expert, Gerard Duart, Laura Gadea Salom, Juan Ortiz Mateu and Ismael Mingarro, from the Department of Biochemistry and Molecular Biology and the Biotecmed Institute of the UV, have also participated in the research. The work was financed by the Generalitat Valenciana and the Ministry of Science and Innovation.