Researchers find a ‘druggable pocket’ in coronavirus that could lead to new antivirals

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Researchers in England say they have made a breakthrough finding that could help defeat the novel coronavirus. Other experts are cautious—they warn potential drug development could take a long time—but say it’s at least a step toward a better understanding of the virus.

As now-familiar images of SARS-CoV-2 show, the virus’s surface is covered with spikes. These so-called spike proteins are able to bind to the surfaces of human cells, leading to infection.

After producing these spike proteins in a test tube, researchers from the University of Bristol took a very close look using a recently developed imaging technique called cryo–electron microscopy, with cloud-based processes, building a 3D structure that they could then examine.

A 3D model of the coronavirus’s spike protein, produced by the Bristol University team.

The structure contained a surprise: pockets containing molecules of an essential fatty acid called linoleic acid (LA), which we absorb via food, and which we need to stay healthy.

Though our bodies don’t make it, they need LA to keep cell membranes fluid, so our lungs can take in oxygen, and to produce substances such as prostaglandin that protect against inflammation in the cardiovascular system.

COVID-19’s symptoms include widespread inflammation and respiratory distress. And studies have shown that people suffering from the disease have lower LA levels than normal. That suggests the virus is scavenging for LA molecules, using them to spread, and harming us in the process.

“We were truly puzzled by our discovery and its implications,” said Imre Berger, who co-led the study, in a statement. “So here we have LA, a molecule which is at the center of those functions that go haywire in COVID-19 patients, with terrible consequences. And the virus that is causing all this chaos, according to our data, grabs and holds on to exactly this molecule—basically disarming much of the body’s defenses.”

With the link between SARS-CoV-2 and LA now having been discovered, the Bristol team hopes it may be possible to turn the virus against itself. The idea is that new small-molecule antiviral drugs could fill these “druggable pockets” so that, once the coronavirus has first entered a patient’s body, it becomes a non-infectious dud that cannot spread.

In an interview with Fortune, Berger said there were two possible clinical routes that could now be taken.

In the shorter term, Berger said, LA could become part of a cocktail of drugs alongside other drugs such as Gilead’s remdesivir, which inhibits another protein in the virus and which has been shown to shorten hospital recovery times for some patients.

LA is nontoxic, and most drugs being considered for coronavirus treatment have side effects, so it is possible that the addition of LA could make it possible to “reduce the amount of other drugs [in the cocktail] to achieve the same beneficial effect,” he said.

In the longer term, Berger suggested, it might be possible to find a molecule that is “even better than LA in closing the spike protein”; the spike protein’s “druggable pockets” seem tailor-made for LA, but that does not mean they cannot take in something else.

This would mean the creation of a new drug for treating COVID-19.

Designer drugs

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said in a statement released through the Science Media Centre that people shouldn’t expect the Bristol discovery to yield new drugs anytime soon, if at all.

But it could prove useful if other measures fail to tackle the coronavirus successfully, he said.

“The cost of any new drugs is likely to be very high and take quite a long time to develop, possibly a longer timescale than for vaccines because it would probably not build as easily onto existing drugs as the vaccines have built on existing vaccines,” Evans said. “If COVID-19 becomes a disease that is not able to be eradicated or brought under control by vaccination and other protective measures, this may offer hope for that longer-term future.”

Regarding the Bristol team’s mention of some relevance with remdesivir, Evans noted that remdesivir still hasn’t shown “really strong reductions in mortality.”

“This is a pandemic, and we don’t have anything at the moment that really works,” Berger said. “We hope and pray the vaccines will work out, but there are no guarantees that any of these vaccines will work. [With HIV] after 30 years of research we do not have a vaccine, but what works is a cocktail of antiviral drugs.”

As for whether the Bristol University paper might lead to the creation of a new stand-alone treatment for COVID-19, the researchers pointed out that a similar discovery of a fatty acid in the cold-causing rhinovirus led to the creation of an antiviral (pleconaril) that proved moderately useful in trials and was licensed for use in emergency cases, though side effects stopped it from being used more widely.

“The linoleic acid–binding pocket in SARS-CoV-2 will make an attractive target for possible designer drugs, lead candidates for which already exist from screens for rhinovirus,” said Michael Skinner, a reader in virology at Imperial College London, in the Science Media Centre release responding to the Bristol paper.

“Drug development and testing is likely to take some time and might have limited effect, or might need to be taken shortly after infection,” said Skinner. “Unless the drugs are already well known and tested, there will also be a need to test well for possible side effects.”

Nonetheless, Skinner and other commentators noted that the Bristol group had a good reputation and had used robust techniques to back up their discovery.

Fortune

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This past weekend saw a flurry of activity in the ongoing saga to sell the U.S. operations of TikTok, the video-streaming app that the Trump administration has threatened to ban if it’s not sold to a U.S. entity. Now, the tentative weekend agreement to save the app from a U.S. ban appears to be hanging by a thread.

On Saturday, U.S. President Donald Trump said he had given his “blessing” to a deal between TikTok’s Chinese parent company, ByteDance, and two U.S. corporations: technology firm Oracle and retail giant Walmart. The deal would reportedly not be an outright sale, but would rather make Oracle and Walmart strategic partners of ByteDance, with Oracle acting as steward of TikTok’s American user data.

In the deal, Oracle and Walmart would reportedly purchase 12.5% and 7.5% stakes, respectively, in TikTok Global, a new ByteDance subsidiary with a value as high as $ 60 billion that ByteDance plans to take public in the next 12 months.

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Interim TikTok CEO Vanessa Pappas declared in a video on Sunday: “We’re here to stay.”

“We are pleased that the proposal by TikTok, Oracle, and Walmart will resolve the security concerns of the U.S. administration and settle questions around TikTok’s future in the U.S.,” a TikTok spokesperson told Fortune on Monday. “We’re thrilled that we will be able to continue serving our amazingly diverse and creative community.”

In a joint Sunday statement, Oracle and Walmart called it a “landmark deal” that would create 25,000 new jobs in the U.S. The statement also said that Americans will hold four of the five spots on TikTok Global’s board of directors, which may include Walmart’s chief executive Doug McMillon and ByteDance CEO Zhang Yiming.

But suddenly, the prospect of a deal turned sour.

On Monday, Trump backtracked from his initial “blessing” of the deal owing to concerns that ByteDance would retain control over TikTok Global.

And on Tuesday, Chinese state media sources said the Chinese government would reject any attempts to diminish ByteDance’s control over TikTok Global.

At the moment, the two sides of the deal—the Trump administration, Oracle, and Walmart on one hand; Beijing and ByteDance on the other—are at loggerheads over whether the new TikTok Global will be majority Chinese- or American-owned, and that sticking point is threatening to derail what, just a day ago, seemed like a done deal.

The initial proposal “seemed like a clear win for Beijing,” says Brock Silvers, former chief investment officer at Adamas Asset Management in Hong Kong, but the U.S.’s new concerns over TikTok Global’s control, access to TikTok’s algorithm, and an education program touted by President Trump threaten to derail the tentative agreement.

“The deal could go either way,” Silvers says. “The odds of a renegotiation or rejection have increased over the last day or two.”

U.S. snags

Over the weekend, Oracle claimed that the TikTok deal would see American shareholders control about 53% of TikTok Global’s shares, because U.S. firms like Sequoia, General Atlantic, and Tiger Management control 40% of ByteDance, TikTok’s parent.

On Monday, Oracle executive vice president Ken Glueck doubled down on Oracle’s position, saying in a statement to reporters that once Oracle and Walmart invest in TikTok Global, the new company’s shares “will be distributed to their owners,” which will leave “Americans” as “the majority.” ByteDance, he said, “will have no ownership in TikTok Global.”

On Monday, ByteDance published an article on the Chinese website Toutiao aimed at dispelling the “rumor” that TikTok Global would be controlled by American investors. ByteDance said on Monday that it would retain an 80% stake in TikTok Global and maintain its control of the technologies and algorithms that power the app.

The deal came under further threat when Trump told Fox News on Monday that U.S. regulators may not approve a deal that didn’t meet Oracle’s standards for U.S. ownership.

“[Oracle is] going to own the controlling interest. Everything is going to be moved into a cloud done by Oracle…and it’s going to be totally controlled by Oracle,” Trump said. “If we find that they don’t have total control, then we’re not going to approve the deal.”

Jeffrey Towson, a private equity investor, said Oracle’s claim that U.S. investors would have a majority stake in TikTok Global is “technically true, but patently false.” Towson said it doesn’t matter if American investors own 40% of ByteDance; that stake doesn’t give them control over how ByteDance—or TikTok Global by proxy—would operate. As ByteDance’s minority owners, they would not be guaranteed a say in ByteDance’s decision-making, he said.

As of now, it remains unclear whether Oracle and ByteDance have agreed to a structure that would cede more of TikTok Global’s potential shares to American ownership. On Tuesday, ByteDance said it had no further comment regarding its negotiations with Oracle.

But Trump’s new demand on Monday that TikTok Global be fully controlled by U.S. investors suggests that the weekend deal didn’t ensure that.

Another, perhaps more minor, area of disagreement emerged on Monday when ByteDance said it was unaware of an agreement that Trump touted that would see the companies involved in the deal contribute to a $ 5 billion “education” fund.

At a Saturday campaign rally, and in a call with top executives from Walmart and Oracle the same day, Trump raised the idea of including the fund as part of the deal. He told supporters at the rally that he’d asked the leaders of the companies involved to put “$ 5 billion into a fund for education, so we can educate people as to the real history of our country.” He added, “That’s their contribution that I’ve been asking for.”

ByteDance denied it had agreed to Trump’s education fund, and responded by saying it was “committed to investing in the education field” and plans to “launch online classroom projects based on A.I. and video technology for students around the world.”

Towson says that the deal proposed this past weekend still makes ByteDance the final decision-maker in terms of how TikTok Global content is moderated and whether or not, for example, political advertising is allowed on the platform. Right now, Towson says, the fact that TikTok’s editor-in-chief “appears to be ByteDance” may still present problems for U.S. regulators.

The China wild card

There is also no guarantee that the Chinese government will sign off on a deal.

In August, the Chinese government introduced restrictions on Chinese companies’ exporting artificial-intelligence technology, meaning that Chinese regulators will likely have to review the deal following approval in the U.S.

Lindsay Gorman, fellow for emerging technologies at the German Marshall Fund of the United States, says that Beijing would likely approve a deal that provided ByteDance with majority ownership of TikTok Global and control over the algorithm that powers the app.

The ability of ByteDance to retain control of TikTok would be a “big win for Beijing,” Gorman said. “Especially if it quiets national concerns among U.S. policymakers.”

Now, with the U.S. government pushing for more control over TikTok Global on Monday, China’s approval may be on shakier ground.

On Monday, China’s foreign ministry spokesperson Wang Wenbin said at a press conference that China would not comment on whether it would approve a potential deal between ByteDance, Oracle, and Walmart. In response to the question, he said China urges the U.S. to “respect the principles of market economy and fair competition” and to “stop politicizing normal trade and economic cooperation.”

Hu Xijin, the editor of the pro-Beijing tabloid the Global Times, suggested that Beijing’s approval of the deal is far from certain. As a top news editor in China, Hu claims to have access to high-level Chinese government sources, but he has a mixed record in predicting China’s official responses to U.S. actions.

“Based on what I know, Beijing won’t approve current agreement between ByteDance, TikTok’s parent company, and Oracle, Walmart, because the agreement would endanger China’s national security, interests, and dignity,” Hu Xijin tweeted on Monday evening Beijing time, as reports emerged that U.S. authorities were pushing for more control over TikTok Global.

As of now, the only thing that appears clear is that the TikTok saga isn’t yet over.

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