“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 anti-apoptotic protein, but we have developed the tools for the future development of inhibitors against any process in which interactions within biological membranes participate”, said Luis Martínez Gil, researcher of the University of Valencia.

Cell apoptosis 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 in which numerous components are involved, among them the family of proteins known as Bcl2 (B-cell lymphoma 2).

The 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 environments (TMD) of Bcl2 family proteins also participate in protein-protein interactions in the membrane and that these are crucial to control programmed cell death.

The transmembrane domain of BclxL establishes interactions within the membrane with members of the Bcl2 protein family, both proapoptotic and antiapoptotic. These interactions are key to controlling the action of the protein, that is, to protect against 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 method, we demonstrated that B-cell lymphoma proteins 2 (Bcl2) interact through their TMD to control programmed cell death or apoptosis. Next, we have designed sequences that recognize and capture the TMD of an anti-apoptotic member of the Bcl2 protein family, which hinders its tumour-inducing properties”, highlighted Luis Martínez Gil, researcher at the University of Valencia.

Apart from Luis Martínez Gil, Gerard Duart, Laura Gadea Salom, Juan Ortiz Mateu and Ismael Mingarro, from the Biochemistry and Molecular Biology Department and the BIOTECMED Institute, from the UV, also participated in the investigation. The work was funded by the Valencian Government and the Ministry of Science and Innovation.

Article: Duart, Gerard et al. «Computational design of BclxL inhibitors that target transmembrane domain interactions». PNAS  2023  Vol. 120  No. 11  e2219648120 https://doi.org/10.1073/pnas.2219648120