Medical Breakthrough! Miniprotiens that can inactive COVID19 virus; PBNS speaks to IISc Researchers

The rapid emergence of new strains of the SARS-CoV-2 virus can potentially threaten the protection offered by COVID-19 vaccines. To overcome this, researchers at the Indian Institute of Science (IISc) Bangalore have developed a new approach that provides an alternative mechanism to render viruses like SARS-CoV-2 inactive. 

As per the researchers, this new class of artificial peptides or mini-proteins can render viruses like SARS-CoV-2 inactive. The study, published in the journal Nature Chemical Biology, states that the mini-proteins can not only block virus entry into our cells but also clump virus particles together, reducing their ability to infect.

In an exclusive conversation with PBNS, one of the brains behind this massive development, Jayanta Chatterjee, Associate Professor in the Molecular Biophysics Unit (MBU), IISc explained to us all about miniproteins and what will be the future of these findings.

What are miniprotiens & How do they prevent viral infections/diseases?

Miniproteins are an upcoming area of study. As the definition goes proteins composed of less than 100 amino acids are classified as miniprotiens. One interesting feature of these molecules is that “they have a very compact structure and a small size which allows them to decorate their surfaces with any functional groups which can then be used to target the spike protein on the surface of the SARS-CoV-2 virus.”

In essence, miniprotiens are a completely new class of molecules, so they certainly are not antibodies, and not small molecules, they fill the gap that lies within.

When you are capable of manufacturing something chemically that is not typically found in nature, we gain an additional handle to alter their structure & make them more stable. 

How does it work against COVID19?

To answer this, the team first tested the miniprotein for toxicity in mammalian cells in the lab and found it to be safe. Next, in experiments carried out in the lab of Raghavan Varadarajan, Professor at MBU, hamsters were dosed with the miniprotein, followed by exposure to SARS-CoV-2. 

These animals showed no weight loss and had greatly decreased viral load as well as much less cell damage in the lungs, compared to hamsters exposed only to the virus. The researchers believe that with minor modifications and peptide engineering, this lab-made miniprotein could inhibit other protein-protein interactions as well. 

What is a protein-protein interaction?

A protein-protein interaction is often like that of a lock and a key. This interaction can be hampered by a lab-made mini protein that mimics, competes with, and prevents the ‘key’ from binding to the ‘lock’, or vice versa. 

In this new study, the team has found an approach to design mini-proteins that can bind to, and block the spike protein on the surface of the SARS-CoV-2 virus. This binding has been further characterised extensively by cryo-electron microscopy (cryo-EM) and other biophysical methods. 

As per the study, these mini-proteins are helical, hairpin-shaped peptides, each capable of pairing up with another of its kind, forming what is known as a ‘dimer’. Each dimeric ‘bundle’ presents two ‘faces’ to interact with two target molecules wherein the researchers have hypothesised that the two faces would bind to two separate target proteins locking all four in a complex and blocking the targets’ action. 

Testing the Hypothesis

The team decided to test their hypothesis by using one of the miniproteins called SIH-5 to target the interaction between the Spike (S) protein of SARS-CoV-2 and ACE2 protein in human cells.  

What is S Protein? It’s a trimer – a complex of three identical polypeptides wherein each one contains a Receptor Binding Domain (RBD) that binds to the ACE2 receptor on the host cell surface. This interaction facilitates viral entry into the cell.  

‘Cross-linking’ S proteins: The SIH-5 miniprotein was designed to block the binding of the RBD to human ACE2. When a SIH-5 dimer encountered an S protein, one of its faces bound tightly to one of the three RBDs on the S protein trimer, and the other face bound to an RBD from a different S protein leading to a ‘cross-linking’ that allowed the mini-protein to block both S proteins at the same time.

The study finds these miniprotein to be ‘thermostable,’ meaning, they can be stored for months at room temperature without deteriorating.

What are the possible usage of microproteins in drug development or in form of any other medicine?

To explore this we need more therapeutic intervention. In our experiments, the molecules were given through intranasal administration to engage the target. Now it depends on where the molecule needs to go, through circulation we need to start the target interaction – this can be done through injection. If the target is in the gastrointestinal tract then we can probably give these molecules orally. 

As of now, we are still trying to access the stability of these molecules against degradation by the enzymes but we can easily design the molecules to be periodically resistant because they are primarily designed to be chemical peptides resistant. We’ll figure out more about the process of delivery as we move ahead with the application of miniprotiens.

Will miniproteins work like vaccines? What would be the possible lasting effects/period of its efficacy once injected or consumed in the body? 

No, these molecules are very very different from vaccines. These Miniproteins could be classified as standard drugs, their duration of action will depend upon pharmacological findings i.e how long these molecules are circulating in the body, and that needs to be thoroughly researched. They could eventually work like antibodies. 

Could there be any side effects of miniprotiens?

The first thing that we need to note is that the ones we have developed are “lab-made miniprotiens,” infact the whole existence of miniprotiens is being taken up as research quite recently. There’s a scope of wider research for the same and it is happening worldwide. So far, we have not noted any such existence of their side effects.

There’s more scope to Miniprotiens and their implications for medicinal use!

We are also currently interested in taking these miniprotiens inside the cells since there are many interesting targets inside them and many antibodies fail to reach them. We would also research more if we can block tumour growth using miniprotiens and injecting them into the cells, then there’s the possibility of testing how they can help in finding treatment for cancers. But all of that needs much extensive research and we are happily looking forward to it. WATCH the Whole Story here: https://twitter.com/PBNS_India/status/1537700320788217857