Known Drugs Being Tried Against the Coronavirus: Runner-Up Candidates
Everyone’s heard plenty about chloroquine, azithromycin, remdesivir and other front-running ideas for anti-coronovirus therapies. Today I wanted to focus on some compounds that haven’t gotten as much attention but which have been proposed from more than one place as possibilities. Some of these have shown up in the comments to past posts here, for example. Do any of them look reasonable? We’ll take four, in no particular order.
First up is Alvesco (ciclesonide), a steroid derivative for asthma, allergies, etc. It’s a glucocorticoid, and there are several of those used for just those indications. But ciclesonide in particular seems to have come up as a hit in drug-repurposing screens, suggesting that it’s not working through its traditional mechanisms. Indeed, there’s now a report that it suppresses replication of the novel coronavirus, but not influenza or RSV. That same paper identifies the viral NSP15 protein (an endonuclease) as the possible target. Repeated passaging of viral infection in the presence of the drug generated a resistant mutant (A25V) of NSP15, which is good evidence. The protein-protein interaction paper that I blogged about yesterday identified NSP15 as targeting human proteins involved in nuclear transport machinery (NUTF2), endocyctic recycling and cytoskeletal remodeling (ARF6) and in evading the innate immune system (through targeting the E3 ligase RNF41/Nrdp1). Those were the main interactions detected for that protein, so it’s possible that ciclesonide is working through disruption of one of those. (That protein-protein paper itself did not pick up ciclesonide as a possible repurposed drug, since it was looking mostly at repurposing known mechanisms, and not completely new hits like this one seems to be). There is a trial getting underway in Japan, in patients who have tested positive but are still asymptomatic, and we’ll see what happens.
The next compound is Niclosamide, which is an antiparasitic drug from the 1950s. Like many compounds in that area, it has a wide range of mechanisms, and has over the years been repurposed for all sorts of things – for example, as a fish poison, particularly for lampreys. Even before this latest epidemic, it had come up in a screenagainst MERS coronavirus infection, apparently through inhibition of autophagy via the human SKP2 protein, and earlier as an inhibitor of replication of the SARS coronavirus as well. One of those repurposing links in the above paragraph that flagged ciclesonide also picked up on this one, so there are several lines of research pointing in the same direction. That said, niclosamide seems to be quite the shotgun, with plenty of side effects (it’s not even frontline therapy any more for its intended use in tapeworm infection). But it’s been in use in humans for many decades (rather like chloroquine, another old drug with known liabilities) and in the current context it seems to deserve a look. It’s not available commercially in the US, from what I can see, and I am not aware of any controlled trials enrolling.
Then we have Disulfiram, which is another very old compound, famously used in the treatment of alcoholism by producing an acute reaction to alcohol intake by inhibition of acetaldehyde dehydrogenase. In effect, drinking while on disulfiram produces an immediate and horrible hangover, complete with headache, nausea, vertigo, and extreme regret. Of course, a person being treated in this way has to be willing to take disulfiram regularly in the full knowledge that if they don’t that they will experience no such symptoms, so it has always been a relatively niche therapy that is not suitable for every patient. It too had already been identified as having activity against the previous coronavirus pathogens for MERS and SARS and was quickly suggested in this current epidemic. It may work through inhibition of cysteine-containing proteases, but this one is another shotgun, and I would be hesitant to assume too much, mechanistically. I believe that the compound has had supply problems, even before this, but there are some trials shown as “Recruiting” on Clinicaltrials.gov, for Lyme and for various oncology indications. Nothing for coronavirus that I’m aware of.
Finally, we have Nitazoxonide, which is an antiparasitic drug from the 1980s and still the only agent approved in the US against Cryptosporidium. You’ll note a broad similarity to niclosamide, above, although the thiazole ring is important (this compound led to an entire class of thiazolides). And being another blunderbuss, it has shown up in several repurposing efforts over time, and a few years ago went into trials as an anti-influenza drug. In vitro and animal model data (see that link) suggests that it would have broader antiviral activity as well. You’d want to see that in the current situation, because any influenza-specific mechanisms would not be expected to carry over well to coronaviruses (as indeed they haven’t). The thing is, nitazoxonide doesn’t seem to have a single broad-spectrum mechanism – as people have studied it against different viruses, different modes of action seem to come up. It has not made it throughall its trials successfully, it has to be noted, but as a broad-spectrum antiviral (one way or another!) it has gotten some attention. I am not aware of any controlled trials underway, although there are reports of its use in the field.