Why Did Folks Think Hydroxychloroquine Would Be Effective Against SARS?

Commenter and Blogger Prof. Joel Eissenberg

Beginning early in the COVID-19 pandemic, Trump, Fox and the right-wing GOP weaponized the disease to sow doubt about science and responsible behaviors. One of the narratives taking hold was that hydroxychloroquine was a cheap, easy and safe cure that scientists were hiding in order to profit from federal dollars for vaccine research.

But in the fog of Trumpian fake news, it is easy to forget that there was a brief period when the science did suggest that chloroquine could have efficacy against SARS-Cov-2. It turns out that this inference was based on a lab artifact. For the virus to infect cells, it “attaches” to the outside of the cell via the viral spike protein (the proteins decorating the viral capsid, giving coronaviruses their “corona”). The spike protein is cut allowing the viral membranes to fuse with the cell membranes and dumping the viral genome inside the cell.

SARS-CoV-2 differs from SARS-CoV because it efficiently uses TMPRSS2, an enzyme found in high amounts on the outside of respiratory cells, to cut the spike protein. But another cell enzyme, cathepsin L, can also do this cleavage in some cells. Cathepsin L normally inhabits cellular endosomes, which are acidic vesicles. Chloroquine works by neutralizing the acid, which makes cathepsin L much less efficient.

The early promising data for chloroquine in the lab turned out to have used cells that rely exclusively on cathepsins for viral entry. But in a natural infection, SARS-CoV-2 doesn’t use endosomes, so chloroquine is ineffective

An important lesson about science is imbedded in this story. Science isn’t about proof, dogma or political fidelity. Science guided by the weight of evidence, and when the evidence changes, science follows the evidence. It’s not “flip-flopping” or mixed messaging. In the fast-moving science of a pandemic, it is important to follow the data, not the political messaging.

How the coronavirus infects cells — and why Delta is so dangerous (nature.com)