MIT Coronavirus Ion Channel Discovery Could Yield New COVID-19 Drugs

Chemists discover the structures of open and closed states of the channel, which could help the development of antiviral drugs to reduce inflammation.

MITMIT is an acronym for the Massachusetts Institute of Technology. It is a prestigious private research university in Cambridge, Massachusetts that was founded in 1861. It is organized into five Schools: architecture and planning; engineering; humanities, arts, and social sciences; management; and science. MIT's impact includes many scientific breakthroughs and technological advances. Their stated goal is to make a better world through education, research, and innovation.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>MIT researchers have discovered the open structure of the SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>SARS-CoV-2 E channel, complementing their previous findings on its closed state. This research could aid in developing antiviral drugs to block the channel and reduce inflammation in COVID-19First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019–22 coronavirus pandemic.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>COVID-19.

Understanding the SARS-CoV-2 E Channel

The genome of the SARS-CoV-2 virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>virus encodes 29 proteins, one of which is an ion channel called E. This channel, which transports protons and calcium ions, induces infected cells to launch an inflammatory response that damages tissues and contributes to the symptoms of COVID-19.

MIT chemists have now discovered the structure of the “open” state of this channel, which allows ions to flow through. This structure, combined with the “closed” state structure that was reported by the same lab in 2020, could help scientists figure out what triggers the channel to open and close. These structures could also guide researchers in developing antiviral drugs that block the channel and help prevent inflammation.

Research Advances

“The E channel is an antiviral drug target. If you can stop the channel from sending calcium into the cytoplasm, then you have a way to reduce the cytotoxic effects of the virus,” says Mei Hong, an MIT professor of chemistry and the senior author of the study.

MIT postdoc Joao Medeiros-Silva is the lead author of the study, which was recently published in the journal Science Advances<em>Science Advances</em> is a peer-reviewed, open-access scientific journal that is published by the American Association for the Advancement of Science (AAAS). It was launched in 2015 and covers a wide range of topics in the natural sciences, including biology, chemistry, earth and environmental sciences, materials science, and physics.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>Science Advances. MIT postdocs Aurelio Dregni and Pu Duan and graduate student Noah Somberg are also authors of the paper.

Investigating Protein Structures

Hong has extensive experience in studying the structures of proteins that are embedded in cell membranes, so when the COVID-19 pandemic began in 2020, she turned her attention to the coronavirus E channel.

When SARS-CoV-2 infects cells, the E channel embeds itself inside the membrane that surrounds a cellular organelle called the ER-Golgi intermediate compartment (ERGIC). The ERGIC interior has a high concentration of protons and calcium ions, which the E channel transports out of ERGIC and into the cell cytoplasm. That influx of protons and calcium leads to the formation of multiprotein complexes called inflammasomes, which induce inflammation.

Structural Insights and Implications

Revealing Atomic-Level Structures

To study membrane-embedded proteins such as ion channels, Hong has developed techniques that use nuclear magnetic resonance (NMR) spectroscopy to reveal the atomic-level structures of those proteins. In previous work, her lab used these techniques to discover the structure of an influenza protein known as the M2 proton channel, which, like the coronavirus E protein, consists of a bundle of several helical proteins.

Early in the pandemic, Hong’s lab used NMR to analyze the structure of the coronavirus E channel at neutral pH. The resulting structure, reported in 2020, consisted of five helices tightly bundled together in what appeared to be the closed state of the channel.

“By 2020, we had matured all the NMR technologies to solve the structure of this kind of alpha-helical bundles in the membrane, so we were able to solve the closed E structure in about six months,” Hong says.

Once they established the closed structure, the researchers set out to determine the structure of the open state of the channel. To induce the channel to take the open conformation, the researchers exposed it to a more acidic environment, along with higher calcium ion levels. They found that under these conditions, the top opening of the channel (the part that would extend into the ERGIC) became wider and coated with water molecules. That coating of water makes the channel more inviting for ions to enter.

That pore opening also contains amino acids<div class="cell text-container large-6 small-order-0 large-order-1">
<div class="text-wrapper"><br />Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called "essential" for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.<br /></div>
</div>” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>amino acids with hydrophilic side chains that dangle from the channel and help to attract positively charged ions.

Channel Dynamics and Drug Development

The researchers also found that while the closed channel has a very narrow opening at the top and a broader opening at the bottom, the open state is the opposite: broader at the top and narrower at the bottom. The opening at the bottom also contains hydrophilic amino acids that help draw ions through a narrow “hydrophobic gate” in the middle of the channel, allowing the ions to eventually exit into the cytoplasm.

Near the hydrophobic gate, the researchers also discovered a tight “belt,” which consists of three copies of phenylalanine, an amino acidAny substance that when dissolved in water, gives a pH less than 7.0, or donates a hydrogen ion.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>acid with an aromatic side chain. Depending on how these phenylalanines are arranged, the side chains can either extend into the channel to block it or swing open to allow ions to pass through.

“We think the side chain conformation of these three regularly spaced phenylalanine residues plays an important role in regulating the closed and open state,” Hong says.

Future Research Directions

Potential for Antiviral Therapies

Previous research has shown that when SARS-CoV-2 viruses are mutated so that they don’t produce the E channel, the viruses generate much less inflammation and cause less damage to host cells.

Working with collaborators at the University of California at San Francisco, Hong is now developing molecules that could bind to the E channel and prevent ions from traveling through it, in hopes of generating antiviral drugs that would reduce the inflammation produced by SARS-CoV-2.

Her lab is also planning to investigate how mutations in subsequent variants of SARS-CoV-2 might affect the structure and function of the E channel. In the Omicron variant, one of the hydrophilic, or polar, amino acids found in the pore opening is mutated to a hydrophobic amino acid called isoleucine.

“The E variant in Omicron is something we want to study next,” Hong says. “We can make a mutant and see how disruption of that polar network changes the structural and dynamical aspect of this protein.”

Reference: “Atomic structure of the open SARS-CoV-2 E viroporin” by João Medeiros-Silva, Aurelio J. Dregni, Noah H. Somberg, Pu Duan and Mei Hong, 13 October 2023, Science Advances.
DOI: 10.1126/sciadv.adi9007

The research was funded by the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>National Institutes of Health and the MIT School of Science Sloan Fund.