Hydroxychloroquine mechanism of action for treating SARS-CoV-2
A new study has been published in Nature, identifying the mechanism of action by which Hydroxychloroquine fights Covid.
https://www.nature.com/articles/s42003-022-03841-8
SARS-CoV-2 bonds with human ACE2 receptors, which the body uses to regulate blood pressure. Apparently the authors have identified a distinct, different mechanism of action in high and low cholesterol contexts; whereby Hydroxychloroquine works to inhibit SARS-CoV-2 in mammalian cells a different way according to whether the tissue is high or low in cholesterol.
They note that SARS-CoV-2 infections were worse when people had high cholesterol or were obese; so what they are saying is that since Hydroxychloroquine works differently in people with high or low cholesterol, and this may explain the difficulty in quantifying its effectiveness – in other words, they say, next time anyone does a study on it, they should differentiate between mice (or cells or people) that have low and high cholesterol, because these are two different mechanisms of action.
The article is highly technical and I do not have sufficient knowledge about microbiology to evaluate the research. Nature is a very well-respected journal, however, and it is peer reviewed.
Here is the abstract:
Hydroxychloroquine (HCQ), a drug used to treat lupus and malaria, was proposed as a treatment for SARS-coronavirus-2 (SARS-CoV-2) infection, albeit with controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the clinic has been hampered by conflicting results. A better understanding of HCQ’s mechanism of actions in vitro is needed. Recently, anesthetics were shown to disrupt ordered clusters of monosialotetrahexosylganglioside1 (GM1) lipid. These same lipid clusters recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to endocytic lipids, away from phosphatidylinositol 4,5 bisphosphate (PIP2) clusters. Here we employed super-resolution imaging of cultured mammalian cells (VeroE6, A549, H1793, and HEK293T) to show HCQ directly perturbs clustering of ACE2 receptor with both endocytic lipids and PIP2 clusters. In elevated (high) cholesterol, HCQ moves ACE2 nanoscopic distances away from endocytic lipids. In cells with resting (low) cholesterol, ACE2 primarily associates with PIP2 clusters, and HCQ moves ACE2 away from PIP2 clusters—erythromycin has a similar effect. We conclude HCQ inhibits viral entry through two distinct mechanisms in high and low tissue cholesterol and does so prior to inhibiting cathepsin-L. HCQ clinical trials and animal studies will need to account for tissue cholesterol levels when evaluating dosing and efficacy.
REFERENCE
Yuan, Z., Pavel, M.A., Wang, H. et al. Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture. Commun Biol 5, 958 (2022). https://doi.org/10.1038/s42003-022-03841-8
