Fighting a Pandemic
The global COVID-19 pandemic has disrupted myriad aspects of modern society, including education, work, travel, the economy, and social interaction. Healthcare workers are fighting tirelessly against the SARS-CoV-2 virus, an invisible and easily transmitted enemy which produces severe respiratory infections and has already led to over 80,000 deaths. Scientists around the world are scrambling to try to pinpoint weaknesses in the virus so that they can develop both vaccines to immunize the uninfected and antiviral drugs to fight the virus in the infected population. Vaccines are usually developed by inactivating the virus or making genetically-altered versions that cannot infect the host. Both should provide the blueprints needed for the body to make virus-fighting antibodies in case an infection occurs later.
But how do we fight off the infection once it’s begun, when antibodies weren’t present or weren’t enough? The scarcity of ventilators and their inability to actually fight off an infection makes the development of antivirals a necessity. The science behind their development, however, is a complex mix of biology, chemistry, and imaging that involves finding a viral target, understanding how it works, and purposely disrupting that key functional mechanisms. Two examples in this battle have recently been published targeting different parts of the viral life cycle. One target would prevent the virus from making copies of itself after it has infected a host cell, and the other would prevent it from invading the cell altogether.
How does a Virus Work?
The goal of a virus is simply to make copies of itself. But unlike other organisms, it cannot do so alone; viruses must hijack the molecular machines inside the cells of its host to duplicate its own genetic material (either DNA or the related RNA molecule) and proteins. Therefore, once inside the body, the virus must first get inside the host cells. This typically involves proteins on the surface of the virus binding to ones on the surface of a cell. This works a lot like a lock and key – the virus cannot enter unless its proteins fit correctly onto the cellular ones. After entering, the virus uses its DNA or RNA as blueprints to make more copies. Unlike cellular proteins, which are made one at a time, viral proteins are often made all at once in a long chain. The final proteins must be freed by cutting the links between them, and this is achieved using something called a protease. After this, the viral copies can be assembled and released when the host cell bursts open. Just like the virus entering the host cell, each step is controlled by highly specific interactions between viral and host molecules. Thus, if scientists can understand how these interactions occur by determining the structure of each involved molecule, then they can develop drugs to prevent viral replication by preventing some part of this process. If we can damage the key or block access to the lock, the virus can’t do what it needs.
Two recent advances sought to do exactly that: Scientists at the Westlake Institute for Advanced Study in China examined the interaction that lets the virus inside the host cell and at the University of Lübeck in Germany identified the structure of the molecule that cuts the links between viral proteins.
There are a number of ways to determine the arrangement of atoms in a molecule. For example, SARS-CoV-2 enters host cells through an interaction between its “S protein” and a protein on the surface of the host cell called ACE2. To study this interaction, biologists used a technique called cryo-electron microscopy, where a beam of electrons irradiates the sample and a detector counts the number of electrons that pass through, similar to how X-rays are used in a CT scan. From this data, the three-dimensional structure of the ACE2 molecule was determined both with and without the bound viral protein, providing insight into how this event allows the virus to enter the host cell.
The German group instead used a technique called X-ray diffraction, which examines how X-rays bounce off the molecules in a crystal. This allowed determination of the structure of the SARS-CoV-2 “main protease,” the molecule that cuts off all the proteins so that the viral copies can assemble. Even more importantly, this group examined the same molecule when a new inhibitor was included. This inhibitor is derived from a molecule that has been shown to be effective in preventing replication of SARS-CoV and MERS-CoV coronaviruses, but was modified by the authors to improve how strongly it binds to SARS-CoV-2. By examining the protease-inhibitor complex, the authors could determine the strength of this interaction to ensure that their modifications had the correct effect and that the inhibitor drug would properly prevent the protease from acting. Understanding the atomic interactions could also aid in identifying further improvements that could make for a better drug.
Structural identification is only the first step in a long process of drug delivery. Next, candidate drugs must be identified, different doses tested in animal or cellular models, and any toxic effects need to be mitigated. Some of these steps were done for the main protease inhibitor, and results showed good drug efficacy in human lung cells and mice along with especially high delivery to lung tissue. Given SARS-CoV-2’s production of respiratory symptoms, this drug could even potentially be inhaled for delivery. Though drug development is a long, complicated process, these two studies are important steps toward winning the battle against COVID-19.
Managing Correspondent: Andrew T. Sullivan
Press Articles: “Crystal structures of the novel coronavirus protease guide drug development,” c&en
“An experimental peptide could block COVID-19,” Medical Xpress
Original Journal Article: “Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors,” Science
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