The spike protein: Decoding the coronavirus’s ‘crown jewel’
Coronaviruses, such as the one currently on a worldwide rampage, are named after the ‘crown’ of spike-shaped proteins that stick out all over their surface, like pins on a pin cushion.
These proteins are not decorative; they are vital weapons in the virus’s arsenal. They grab onto other proteins called receptors on the surface of our cells, allowing the virus to break into them.
The spike protein is the most sought-after target for new drugs and vaccines because it is abundant on the virus’s surface and plays a crucial role in viral entry. To aid these efforts, scientists have been racing to understand what it looks like, and how it differs from those of other coronaviruses.
Mapping spike structure
Spike proteins of all coronaviruses have three segments: an outer-facing part, a stalk that spans the virus’s envelope and a short tail inside. The outer-facing part has two regions: a three-headed S1 subunit and an S2 subunit. To kick-start virus entry, S1 first binds to the host cell receptor, and then S2 fuses with the host cell membrane, creating a channel for the virus to inject its genetic material inside. S1 has distinct sites called receptor binding domains that match complementary sites on the cell’s receptor, like two pieces of a puzzle.
Studies have shown that the spike protein of the novel coronavirus is very similar to that of the 2003 SARS virus, and binds to the same receptor: an enzyme called ACE2.
In February 2020, researchers from the University of Texas at Austin and the National Institutes of Health constructed the first 3D ‘map’ of the protein in its pre-fusion state, using a powerful technique called Cryo-Electron Microscopy. They rapidly froze copies of the protein made in the lab, and reflected electron beams off of them to form patterns that they used to piece together the protein’s structure.
Reconstructing the spike structure helped the researchers draw important comparisons with other coronaviruses. They found, for example, that S1 switches from a ‘down’ state, where its receptor-binding parts are hidden, to an ‘up’ state where they are exposed, similar to that of other coronaviruses. Crucially, the spike protein of the novel coronavirus was able to bind to the receptor 10-20 times more tightly than that of the SARS virus, which might explain why the former is more infectious.
In March, researchers from the University of Minnesota delved deeper into the protein’s structure. Using X-ray crystallography, they discovered a molecular “ridge” which was more compact in this protein compared to that of the SARS virus. This, among other differences, allows it to form a greater number of bonds with a cell’s receptor.
Several research groups have spotted another key difference: a unique cleavage site. Once it binds to a receptor, the spike protein needs to be cut into two, which prompts S1 to be cast off and S2 to transform and fuse with the host cell membrane. The novel coronavirus recruits an enzyme called furin found in our cells to chop the spike protein at a unique site along the S1/S2 boundary. This site is not found in the SARS virus, but similar sites have been reported in other highly infectious viruses. Furin is found in cells throughout our body, especially the lungs ‒ another possible reason why the virus is able to spread so easily. The S1/S2 site also appears to form an extended loop that sticks out ‒ unlike in the SARS virus, where it is compact ‒ making it an easier target for enzymes to cut.
There is also evidence that the spike proteins are coated with sugars that may be shielding the virus from our immune system.
Such clues are important because they help scientists decide which parts of the spike protein to target, and design drugs and vaccines accordingly.
Targeting the spike
The spike protein is already the basis for several vaccine development efforts around the world. Because it is plentiful on the virus’s outer surface, it can easily be recognized by our immune system. Injecting vaccines containing the whole spike protein or parts of it can trigger our immune system to produce antibodies that can fight the virus if it shows up later.
It is also the target of antibody-based therapies that are being heralded as stopgap treatments until a vaccine is developed. These involve giving patients antibodies made in the lab against the spike protein, with the hope that they will bind to the virus and block infection. Such antibodies have previously worked well in cancer treatment. Several companies such as Regeneron and AstraZeneca are working on such therapies.
Researchers are also testing a new type of antibody generated using llamas to target the spike protein. In addition, experimental peptides ‒ short strips of synthetic proteins that resemble the receptor, and bind to the spike protein ‒ are also being explored.
Ranjini Raghunath is a Communications Officer at the Office of Communications, Indian Institute of Science (IISc)