AsianScientist (Feb. 13, 2020) – Each month, the Protein Data Bank (PDB) highlights a relevant molecule from its repository of over 160,000 biological structures. Perhaps in its most serendipitous selection yet, the Molecule of the Month for February is none other than the COVID-19 protease, which resembles the symbol of a heart.
Though microscopic, COVID-19—previously known as novel coronavirus 2019 (nCoV-19)—has brought once-bustling cities to a standstill as governments and public health officials try to contain the epidemic. With over 1,000 deaths and 45,000 cases worldwide, experts remain unsure if the worst is over or if it is yet to come.
At the frontlines of the battle against COVID-19 are healthcare workers, who risk their lives daily as they screen, diagnose and treat those infected. But hard at work behind the scenes are scientists racing to understand the virus, in hopes of finally ending the outbreak.
Structural biologists, in particular, play a crucial role. Like assembling the pieces of a particularly challenging puzzle, structural biologists use advanced imaging techniques to determine the intricate, three-dimensional structures of biological molecules like COVID-19, as seen above. Researchers can then use this knowledge to design or guide their search for novel antiviral drugs.
A tale of two subunits
COVID-19 belongs to a subset of viruses known as coronaviruses—so called for the ‘crown’ of proteins that dot the viral surface. Underneath its royal exterior lies a lengthy strand of ribonucleic acid (RNA), which serves as the viruses’ genetic material. When COVID-19 infects a cell, it hijacks the existing molecular machinery to create long chains of proteins required by the virus to generate even more copies of itself.
These long viral proteins, however, only become functional when cut into smaller pieces by proteases. Thus, coronavirus proteases like that of COVID-19’s play an integral role in propagating the virus. As seen in the diagram, its distinctive heart shape is the result of two identical protein subunits (colored orange and red) coming together to form a functional protease.
Similar to a lock and its key, the protease’s activity is triggered by the binding of molecules to specific points on the protease called active sites. The binding of a substrate effectively switches the protease on, allowing it to cut the long viral protein strands into smaller chains.
Searching for a heart-stopper
In the same way, the protease’s activity can also be blocked by molecules called inhibitors. When an inhibitor (depicted in turquoise) attaches to an active site, it prevents the binding of substrates—stopping the action of the protease altogether. Therefore, finding an inhibitor for COVID-19’s heart-shaped protease may be the first step to beating the epidemic.
Alas, some things are easier said than done. Coronaviruses and their proteases are a diverse bunch, so inhibitors for one type of coronavirus may not work for COVID-19. But examining the protease structure of related coronaviruses, like those found in bats, may help identify inhibitors against COVID-19 and other emerging viruses.
Another approach may be to repurpose existing antiviral drugs. For instance, a cocktail that includes HIV drugs lopinavir and ritonavir—both protease inhibitors—has seen early success in treating patients with severe cases of COVID-19. Even so, it’s too early to tell if this cocktail could become a standard treatment. Until then, the search for a way to stop COVID-19’s heart-shaped protease continues.
Copyright: Asian Scientist Magazine.
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