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Scientists create proteins that do not exist in nature and that mimic the immunoglobulins of antibodies

Computational design has made it possible to create proteins that mimic the folded immunoglobulin structure of natural antibodies. They can be used as a basis for the development of tailor-made and more economical antibody-like drugs. These results open the door to the design of antibody-like proteins with tailored structures and better biophysical properties than current ones.

Estructura de una de las inmunoglobulinas diseñadas por los investigadores, con una zona de unión a calcio (IBMB/CSIC)

Current drugs based on monoclonal antibodies are currently among the most promising and breakthrough drugs in the pharmaceutical industry, especially for the treatment of different types of cancer, autoimmune diseases and, more recently, viral infections. They are based on modifying a small region of the antibodies to specifically recognise and attack specific targets, such as cells or virus, among others.

However, these drugs are still costly therapies as there are limitations that slow down their progress, such as low stability, large size and difficult large-scale production, among others. That’s why they are highly expensive drugs to develop, to produce and, as they are very unstable, also difficult to distribute, because appropriate storage and refrigeration conditions are required for their preservation. 

Scientists from the Spanish Council for Scientific Research at the Barcelona Institute of Molecular Biology (IBMB-CSIC) and from the Institute for Protein Design at the University of Washington have carried out a research that could help to overcome these limitations.

They have designed and created proteins that do not exist in nature and whose structure mimic the folded immunoglobulins of antibodies. The new proteins could serve as a basis for the development of more affordable monoclonal antibody-based drugs. The study is led by Enrique Marcos and F. Xavier Gomis Rüth, both from IBMB-CSIC, and David Baker, from the Institute for Protein Design at the University of Washington. The results were recently published in the journal Nature Communications.

Current difficulties in modifying antibodies

The part of the antibodies that is modified is a very specific one. "All antibodies have a very similar structure, but at their ends they differ in a small variable region that allows each antibody to specifically recognise a target," explains Enrique Marcos. This variable region is a scaffold with folded immunoglobulins, which are suited for anchoring antigen-binding hypervariable loops to interact and recognise specific pathogens.

They have generated new proteins and checked by crystallography that the structures obtained were those predicted in the models, which means that "we can design the proteins with high accuracy".

The research that has just been published describes a computational strategy to design "small immunoglobulins like those of antibodies with customised structures, high stability and with the capacity for anchoring flexible areas with the capacity to bind to the desired target," explain the scientists.

The scientific team has followed this computational strategy to generate the new molecules. Afterwards, they checked by crystallography that the structures obtained were those predicted in the models, which means that "we can design the proteins with high acccuracy," adds Marcos.

The work, in which teams from the University of Toronto (Canada) have also participated, opens the door to the design of antibody-like proteins with tailor-made structures and better biophysical properties than current monoclonal antibodies, which would be a breakthrough for the development of more accessible drugs and enable new mechanisms of action.

Referencia:

Tamuka M. Chidyausiku, Soraia R. Mendes, Jason C. Klima, Marta Nadal, Ulrich Eckhard, Jorge Roel-Touris, Scott Houliston, Tibisay Guevara, Hugh K. Haddox, Adam Moyer, Cheryl H. Arrowsmith, F. Xavier Gomis-Rüth , David Baker & Enrique Marcos. De novo design of immunoglobulin-like domains,   Nature Communications volume 13, Article number: 5661 (2022) https://doi.org/10.1038/s41467-022-33004-6