Thursday, 13 Dec 2018

Mexican scientists design synthetic proteins

  • Mexican scientists collaborated in the creation of de novo proteins that interact with botulism toxin and H1 influenza hemagglutinin
  • De novo proteins are those molecules that have an amino acid sequence that does not exist in nature

Three Mexican scientists were part of a research group that created and documented a new high-throughput method to produce thousands of synthetic proteins, under the direction of David Baker, head of the Protein Design Institute at the University of Washington, United States.

In the project, Daniel Adriano Silva Manzano, postdoctoral researcher granted a scholarship by the National Council of Science and Technology ( Conacyt ) at the University of Washington, as well as Daniel Alejandro Fernández Velasco, doctor in basic biomedical research, and Renan Vergara Gutiérrez, student of the doctorate in biochemical sciences, both belonging to the Physicochemistry and Protein Engineering Laboratory of the Faculty of Medicine of the University National Autonomous Government of Mexico (UNAM).

Mexican scientists collaborated in the creation of de novo proteins that interact with the botulism toxin and H1 influenza hemagglutinin. De novo proteins are those molecules that have an amino acid sequence that does not exist in nature, that is, they are synthetic and developed entirely from a computer platform.

Traditionally, proteins are isolated from organisms (such as bacteria or fungi) and then used as therapeutic agents, but recent advances in computer design allow the generation of synthetic proteins with new functions or improve the characteristics of natural proteins for medical purposes. and biotechnology. The first time a protein was designed by computer was in 2003. Since then, the computational design of more than 20 different proteins has been reported.

Methodology for the design of de novo proteins for influenza and botulism

Through the Rosetta computer platform, developed by Dr. David Baker and collaborators, the researchers designed the skeleton (structure) of the protein.

With previous knowledge of the structure of the neurotoxin that causes botulism and the outer proteins of the influenza virus, it is feasible for researchers to design a protein that binds to those that cause the damage, in this case, the viruses PR8 and CA09 of influenza and botulism BoNT-B toxin.

“The program allows us to find a complementary structure capable of recognizing the protein we want to attack. First the skeleton of the protein is designed and then the details of it, that is, the side chains. We studied the external form of the molecule to see where our synthetic protein could be used to interact with another molecule and attack it, “said Daniel Alejandro Fernández.

With the system it was possible to design thousands of proteins that could bind to influenza hemagglutinin and botulinum neurotoxin B.

Once the synthetic proteins were designed, experiments were carried out in vivo with laboratory mice to verify the efficacy of some of them. On the one hand, the designs provided prophylactic and therapeutic protection against influenza. While designs for botulism prevented toxins from entering brain cells in laboratory animals.

“The designs were able to neutralize the PR8 and CA09 viruses of the influenza virus. The intranasal administration of protein in mice managed to protect them from infection, with a 100 percent survival rate. On the other hand, the designs made for botulism prevented the entry of BoNT-B toxin into rat cortical neurons, as well as the proteolysis of the synaptobrevin protein (VAMP2), “explained Renan Vergara.

Benefits of technology

The ability of synthetic proteins to perform interactions of very high affinity and specificity with the molecule to be attacked, enables the development of drugs with fewer side effects. In addition to being more stable compared to certain natural proteins such as antibodies. Once designed they can be stored without the need for refrigeration. According to Daniel Alejandro Fernández, the above facilitates the management of these proteins.

“Most of the drugs that are consumed have secondary effects because the proteins do not stick directly to those that we want to attack or perform an effect (for example, BoNT-B botulism toxin), but in many others; this causes a large number of side effects and then as the design of the drug becomes thinner, the molecules that are used are those that are designed to interact with one molecule and not with the others, “he says.

Technology in Mexico

In Mexico, there are several research groups that use the software Rosetta with the aim of designing proteins with new functions and improving the characteristics of natural proteins.

“Unfortunately, assembling the necessary methods for the selection of designs that meet the desired characteristics requires a significant economic investment, which is a limitation for the design of proteins to reach a broad growth in the country,” said Renan Vergara.

According to Renan Vergara, de novo protein design enables the development of treatment to combat various diseases. In the case of viral or bacterial infections, proteins can be developed that interact with the cell surface proteins involved in the infection process and prevent their recognition by pathogens.

With information from Conacyt

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