Hydroxychloroquine Is Toast. Now Say Hi to Its ‘Dirty’ Cousin

There have been multiple funerals, by now, for hydroxychloroquine, a decades-old malaria drug that has been touted as a cure for Covid-19. Although US President Donald Trump once took the medicine as a prophylactic—and even now insists that it would be “the hottest thing going” if not for biased media coverage—hydroxychloroquine was a flop in clinical trials, and in June the US Food and Drug Administration revoked its emergency approval for use in fighting the pandemic. The proverbial nail in the coffin—which I helped hammer in—was the revelation that early research on the drug’s efficacy against Covid-19 had used the wrong type of cells. Now that rollercoaster may be starting on a second trip: New experiments on hamsters suggest that a close chemical cousin to hydroxychloroquine, called amodiaquine, might also hold some promise against the pandemic virus.

The surprising study became available on the preprint server bioRxiv on August 19. Its authors describe how they dosed a couple dozen hamsters with amodiaquine and then spritzed the rodents’ noses with the new coronavirus. The animals continued to receive amodiaquine for three more days, and then were checked against a control group that did not receive the drug. Hamsters treated with amodiaquine ended up with 70 percent less genetic material from the virus in their lungs. In a second study, the researchers started healthy hamsters on amodiaquine, then put them in a cage with others that were sick. Again they did much better than their control-group counterparts: Treated animals ended up with 90 percent less viral material in their lungs.

The researchers have submitted their paper for publication in a scientific journal, but it has not yet undergone formal review for errors by their scientific peers—and they stress that it’s a far leap from hamsters to humans. Amodiaquine is one of a smattering of drugs that have shown some efficacy against the pandemic virus in laboratory animals. But given its close connection to hydroxychloroquine, the emergence of this drug in particular as a candidate for further research could be quite significant. For many around the world, it could also be quite dangerous.

Amodiaquine was first synthesized in the mid-1940s, at a time when scientists were making artificial versions of the antimalarial compound quinine, which is found in the bark of the cinchona tree. (During World War II, supply chains for cinchona bark were compromised, so alternatives became important.) Amodiaquine’s molecular structure is very similar to those of chloroquine and hydroxychloroquine, the latter of which was discovered around the same time. During the 1970s, it was tested in owl monkeys, and then in human trials, and found to be an especially useful therapy for chloroquine-resistant strains of malaria.


Illustration: National Library of Medicine/PubChem


Illustration: National Library of Medicine/PubChem

But from a pharmaceutical point of view, there’s at least one major difference between these drugs. Benjamin tenOever, a microbiologist at the Icahn School of Medicine at Mount Sinai in New York and one of the authors of the new study, describes amodiaquine as being “dirtier” than its cousins. That means that its effects on cells are more spread out, hitting a greater variety of molecular targets. As biochemist Bryan Roth once told Nature, a dirty drug may be less like a “magic bullet” than a “magic shotgun.”

Still, after all the hype and then deflation over hydroxychloroquine, he didn’t see much reason to be excited for amodiaquine. Both drugs had been tested against a wide range of diseases such as Ebola, Zika and even Dengue virus, with mixed results. Amodiaquine, like hydroxychloroquine, showed promise against the original SARS virus and the related Middle East Respiratory Syndrome virus—though these experiments (like the early ones on hydroxychloroquine and Covid-19) were done using monkey kidney cells, which don’t offer a great model for what happens in the human lung. But in April, tenOever’s funders at the US Defense Advanced Research Projects Agency asked him to run the tests. “I was really reluctant to do it,” he says, “but we did eventually come to try.”

The first time tenOever and his collaborators gave the drug to hamsters in his lab, in early June, it offered considerable protection against the virus that causes Covid-19. “We thought, ‘Oh, OK, that was weird. Let’s do it again,’” tenOever says. They kept repeating it and seeing good results. The research team, which includes Donald Ingber of the Wyss Institute in Boston, had already shown that, in human lung cells, the drug reduces levels of a harmless virus engineered to carry the same spike protein as the pandemic one. “It works beautifully,” tenOever says.