Controlling CORONA virus infections is basically the lock and key issue. Only the right key can open or lock the door locker. There are several spike proteins on the surface of Corona virus we can consider as locks. A proper chemical that can bind to the spike protein can bind the receptor binding proteins on the cells and inactivate the virus stopping penetration that would start infection.
We have all seen the images of the SARS-CoV-2 virus that causes Corona Virus (COVID 19). Researchers are working to develop monoclonal antibody therapies to combat the virus. Antibodies against corona virus are such keys that tightly bind to the spike proteins and prevent the virus from binding to the cells. Several companies are developing vaccines that can produce specific antibodies against the virus. Some of the vaccines are large and sensitive molecules requiring refrigeration and also have short shelf life making them difficult to be used for large scale trials over longer periods. Instead of vaccination, one can deliver pre-generated (passive) antibodies (REGENERON®) to the infected individuals.
Researchers led by Dr. David Baker of the University of Washington set out to design synthetic “miniproteins” that bind tightly to the coronavirus spike protein. Their study was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS) and National Institute of Allergy and Infectious Diseases (NIAID). Findings appeared in Science News on September 9, 2020.
The team used two strategies to create the antiviral miniproteins. First, they incorporated a segment of the ACE2 receptor into the small proteins. The researchers used a protein design tool they developed called Rosetta blueprint builder. This technology allowed them to custom build proteins and predict how they would bind to the receptor. It is similar to going to “locksmith” (ACE2 receptor protein) and ordering a key that would fit the corona virus (spike protein) lock.
The second approach was to design miniproteins from scratch, which allowed for a greater range of possibilities. Using a large library of miniproteins, they identified designs that could potentially bind within a key part of the coronavirus spike called the receptor binding domain (RBD). In total, the team produced more than 100,000 miniproteins.
Next, the researchers tested how well the miniproteins bind to the RBD. The most promising candidates then underwent further testing and tweaking to improve binding. Using cryo-electron microscopy, the team was able to build detailed pictures of how two of the miniproteins bound to the spike protein. The binding closely matched the predictions of the computational models.
Finally, the researchers tested whether three of the miniproteins could neutralize corona virus (SARS-CoV-2). All miniproteins protected lab-grown human cells from infection. Candidates LCB1 and LCB3 showed potent neutralizing ability. These were among the designs created from the miniprotein library. Tests suggested that these miniproteins may be more potent than the most effective antibody treatments reported to date.
“Although extensive clinical testing is still needed, we believe the best of these computer-generated antivirals are quite promising,” says Dr. Longxing Cao, the study’s first author. “They appear to block SARS-CoV-2 infection at least as well as monoclonal antibodies but are much easier to produce and far more stable, potentially eliminating the need for refrigeration.”
Notably, this study demonstrates the potential of computational models to quickly respond to future viral threats. With further development, researchers may be able to generate neutralizing designs within weeks of obtaining the genome of a new virus. The implication of this development goes beyond infection control and can lead to prevention of several disorders such as allergic reactions where binding two molecules can be effectively controlled.