Experimental Mutant Peptide Could Target and Disable COVID-19 Virus: Study
Wed, April 21, 2021

Experimental Mutant Peptide Could Target and Disable COVID-19 Virus: Study

 

A new study showed an experimental peptide designed to target SARS-CoV-2, the virus of COVID-19. Scientists used computer modeling to determine its capabilities, and they found that the peptide could attach and disable the pathogen.

The investigational peptide for COVID-19 was modeled and analyzed by scientists at the Massachusetts Institute of Technology (MIT), a private research university in the US. Their computational modeling suggested that the peptide could attach, bind, and destroy SARS-CoV-2. The ability of the peptide to bind was based on the ACE2 receptor, the critical requirement for the virus to infect human cells. They published their findings in the journal bioRxiv.

New Peptide to Stop COVID-19

Researchers around the world are investigating various methods to create new therapies for COVID-19. Any positive yields will help healthcare workers and patients in this pandemic. New therapies that work can be deployed to flatten the curve of infection rate globally. This is one way to control the global crisis while everyone waits for a functional vaccine. At the same time, proven therapies will become a standard treatment for future COVID-19 cases, since many experts are believing that the disease may become a part of human societies, like the common cold and influenza.

At MIT, scientists utilized computer models and enzymes to formulate proteins capable of disabling the virus, similar to how human antibodies work. However, the proteins have to strongly target and hold the virus in place, which can ensure the safety of human cells. Simultaneously, the proteins must not attack human cells or trigger an immune response that can defeat the main purpose. So, they focused their efforts on antibodies and related principles.

One of the current interests in SARS-CoV-2 has been its spike protein. It is a critical part of the lock-and-key mechanism used by the virus to infect host cells. The spike protein requires the ACE2 receptor on the surface of human cells. Once attached, the spike protein unlocks the interior part of a host cell, making it vulnerable to the virus. From here, the virus can hijack and take over the machinery of the infected cell, allowing the pathogen to create more copies.

While the immune system can generate antibodies to the novel coronavirus, it takes time to produce these proteins. As such, people who are infected may develop symptoms within 14 days after contracting the virus. If their body handled the infection, they will produce antibodies without suffering from symptoms. But if their body failed to handle the situation, they will likely experience symptoms and develop associated complications. By the time the antibodies are ready, multiple organ systems are in bad shape.

Instead of manufacturing antibodies, the team designed peptides to do the job. To create these peptides, they applied a computational model trained to simulate the interactions of proteins. They also used similar computational models specifically applied in improving the enzymes for CRISPR, a gene-editing tool. The new enzymes could target over 70% of DNA sequences, significantly higher than the 10% performance rate of enzymes from the most common CRISPR form.

 

 

The creation of peptides started in the human ACE2 protein that the SARS-CoV-2 binds to. The computer models were deployed to break the human protein into smaller fragments. Then, the interactions of the fragments with the spike protein were analyzed. After that, the model was instructed to optimize three features for the peptides.

The first optimization was the strong binding affinity to the spike protein. This would ensure the attachment to SARS-CoV-2. The second was the enhanced binding affinity to spike proteins of other coronaviruses. In case the peptides worked in clinical settings, it could be exploited to address known and unknown coronaviruses. Third, the peptides were optimized not to strongly bind to integrins, human proteins involved in the ACE2 receptor.

The optimization resulted in 25 candidate peptides, all of which fused by scientists to an E3 ubiquitin ligase. The fused peptides were tested in human cells that led to the expression called receptor-binding domain or RBD, a fragment of the spike protein. The best candidate from these peptides was the 23-amino-acid peptide that broke down around 20% of the RBD proteins in cells. Though, its efficiency was not on par with the original ACE2 protein, which could break down RBD proteins by 30%.

For improving the candidate peptide, computer modeling was applied again to predict how it would perform if various amino acids in each of the peptide's 23 positions were substituted. The model predicted a mutant peptide thatr could break down more than 50% of RBD proteins. Another key trait of this mutant peptide is its size – only 200 amino acids in length even if fused with E3 ubiquitin ligase. This peptide's genetic coding could be delivered harmlessly by adeno-associated viruses into the human body.

If those viruses are not selected, another possible method of delivering the genetic code would via direct introduction. The peptide could be introduced to the body to bind to the spike protein of SARS-CoV-2. When bound, the virus would be disabled and carried by the peptide into the cell. Since it's disabled, the cell would recognize it as foreign and tag it for destruction.

 

 

The Staggering Cases of COVID-19 Pandemic

According to the World Health Organization of the United Nations, the worldwide total of confirmed cases was 9,296,202, as of June 25, 2020, while the global total of confirmed deaths was 479,113. The Americas remained with the highest confirmed cases and confirmed deaths at 4,604,134 and 230,165, respectively. Despite the continuous reporting of new cases, the Western Pacific had the lowest confirmed cases at 209,215. Africa remained with the lowest confirmed deaths at 5,441.

The report posted by the organization on that date confirmed the end of the 10th Ebola virus disease outbreak in the Democratic Republic of the Congo. This would greatly help the country realign its resources to COVID-19. The same measures the government used for Ebola could be applied to suppress COVID-19 outbreaks. Thus, trained healthcare workers for containing and managing Ebola were redeployed to fight the pandemic.

The MIT scientists are now planning to test the mutant peptide in human cells already infected by SARS-CoV-2. They have to determine if the peptide can disable the virus from the inside. Because of the objective, that research is set to be conducted in specialized biosafety laboratories.