The research summary is a brief overview of interesting academic work.
The big idea
On July 22, an article came out in Nature that further highlights previous studies showing that neither the anti-malaria drug hydroxychloroquine nor chloroquine prevent SARS-CoV-2, the virus that causes COVID-19, from replicating in lung cells.
Most Americans probably remember that hydroxychloroquine became the focus of numerous clinical trials following the President’s statement that it could be a “game changer.” At the time, he seemed to base this claim on anecdotal stories, as well as some very limited early studies that hydroxychloroquine seemed to help COVID-19 patients recover.
Many in the antiviral field, including myself, questioned the validity of both, and in fact, one of the articles was belittled by the scientific society and the editor of the magazine that published it.
Since then, HQC has had a bumpy ride. It was initially approved by the FDA for emergency use. The FDA quickly reversed its decision when numerous reports of deaths from cardiac arrhythmias emerged. That news stopped many clinical trials. Still, some scientists continued to study it in hopes of finding a cure for this deadly virus.
How the work was done
The new study was conducted by scientists in Germany who tested HCQ on a collection of different cell types to discover why this drug does not prevent the virus from infecting humans.
Their findings clearly show that HQC can block the coronavirus from infecting African green monkey kidney cells. But it does not inhibit the virus in human lung cells, the primary site of infection for the SARS-CoV-2 virus.
In order for the virus to enter a cell, it can do so by two mechanisms: one, when the SARS-CoV-2 tip protein binds to the ACE2 receptor and inserts its genetic material into the cell. In the second mechanism, the virus is absorbed into some special compartments in cells called endosomes.
Depending on the cell type, some, such as kidney cells, need an enzyme called cathepsin L for the virus to infect them successfully. However, in lung cells, an enzyme called TMPRSS2 (on the cell surface) is necessary. Cathepsin L requires an acidic environment to function and allow the virus to infect the cell, whereas TMPRSS2 does not.
[[[[Deep, daily knowledge. Sign up for The Conversation newsletter.]In green monkey kidney cells, both hydroxychloroquine and chloroquine decrease acidity, which then deactivates the cathepsin L enzyme, blocking virus infection by monkey cells. In human lung cells, which have very low levels of the cathepsin L enzyme, the virus uses the enzyme TMPRSS2 to enter the cell. But because that enzyme is not controlled by acidity, neither HCQ nor CQ can block SARS-CoV-2 from infecting the lungs or stopping the virus from replicating.
Because it is important
This is important for several reasons. One, you have spent a lot of time and money studying a drug that many scientists said from the beginning was not going to be effective in killing the virus.
The second reason is that studies that reported antiviral activity for hydroxychloroquine were not performed on lung epithelial cells. Therefore, their results are not relevant to adequately study SARS-CoV-2 infections in humans.
Whats Next?
As scientists continue to research new drugs and try to reuse old ones, such as hydroxychloroquine, it is critical that researchers take time to think about their study design.
In summary, those of us involved in the development of antiviral drugs should learn a lesson from this study. It is important not only to focus our efforts on finding drugs that directly turn off viral replication, but also to study the virus at the primary site of infection.
Katherine Seley-Radtke, professor of chemistry and biochemistry and president-elect of the International Society for Antiviral Research, University of Maryland, Baltimore County
This article is republished from The Conversation under a Creative Commons license. Read the original article.
