The scientists, in experiments described in a paper published January 6, 2022 in the journal Antioxidants, found that the compound, carnosic acid, can block the interaction between the SARS-CoV-2 outer "spike" protein and the receptor protein, ACE2, which the virus uses to gain entry to cells.
The team also presented evidence, and reviewed evidence from prior studies, that carnosic acid has a separate effect in inhibiting a powerful inflammatory pathway - a pathway that is active in severe COVID-19 as well as in other diseases including Alzheimer's.
"We think that carnosic acid, or some optimized derivative, is worth investigating as a potentially cheap, safe, and effective treatment for COVID-19 and some other inflammation-related disorders," says study senior author Stuart Lipton, MD, PhD, Professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research.
In a 2016 study, Lipton and colleagues showed that carnosic acid activates an anti-inflammatory, antioxidant signaling cascade called the Nrf2 pathway, and found evidence that it reduces Alzheimer's-like signs in mouse models of that disease, which is known to feature brain inflammation.
For the new study, Lipton, along with Chang-ki Oh, PhD, and Dorit Trudler, PhD, respectively a staff scientist and postdoctoral fellow in the Lipton lab, and first author Takumi Satoh, PhD, of the Tokyo University of Technology, described their further studies of this anti-inflammatory effect on the immune cells that drive inflammation in COVID-19 and Alzheimer's. The researchers also reviewed evidence from other investigators’ studies indicating that carnosic acid inhibits inflammation in other disease models. They proposed that this effect could be beneficial against the inflammation observed in COVID-19 and in some cases of the post-COVID syndrome known as long COVID, whose reported symptoms include cognitive difficulties often described as "brain fog."
Additionally, the scientists described a COVID-19 infection-blocking experiment conducted by Oh. Using a standard infectivity assay, he showed that carnosic acid can directly block SARS-CoV-2’s ability to infect cells, with progressively greater infection-blocking activity at higher doses.
While the research is preliminary, the researchers propose that carnosic acid has this antiviral effect, despite being a safe and relatively unreactive compound, because it is converted to its active form by the inflammation and oxidation found at sites of infection. In that active form, they suggest, the compound modifies the ACE2 receptor for SARS-CoV-2 - making the receptor impregnable to the virus and thereby blocking infection.
"Carnosic acid represents a ‘pathologically activated therapeutic' in preclinical models of disease - inactive and innocuous in its normal state, but converted to an active form where it needs to be active," Lipton says.
Lipton and his colleagues are now working with Scripps Research chemists, including Phil Baran and Ben Cravatt, professors in the Department of Chemistry, to synthesize and test more potent derivatives of carnosic acid with improved drug characteristics for potential use in inflammation-related disorders.
Lipton and Satoh hold patents for the use of carnosic acid derivatives for degenerative diseases.
Satoh T, Trudler D, Oh CK, Lipton SA.
Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer's Disease, Parkinson's Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome.
Antioxidants (Basel). 2022 Jan 6;11(1):124. doi: 10.3390/antiox11010124