COVID-19 continues to claim lives around the world and is infecting millions more. Although several vaccines have recently become available, making significant strides towards preventing COVID-19, what about the treatment of those who already have the infection?
Vaccines aren’t 100% effective, highlighting the need – now more than ever – for effective antiviral therapeutics. Moreover, some people can’t receive vaccines due to health issues, and new variants of SARS-CoV-2, the virus that causes COVID-19, that can penetrate vaccine-conferred immunity, are being reported, indicating that we need to think beyond prevention.
Given this need, a team of researchers based in Japan, the US, and the UK launched a project to develop effective therapeutics.
This team included several researchers based at Tokyo University of Science: Visiting Professor Koichi Watashi, Dr. Hirofumi Ohashi, Professor Shin Aoki, Professor Kouji Kuramochi, and Assistant Professor Tomohiro Tanaka. Their goal was clear and simple: finding a cure for COVID-19.
To achieve this goal, the researchers first established an experimental system for screening drugs that may help to control infections. This system used a type of cells called VeroE6/TMPRSS2 cells, which were manipulated to efficiently be infected with and produce SARS-CoV-2.
“To determine whether a drug of interest could help combat infection by SARS-CoV-2, we simply had to expose VeroE6/TMPRSS2 cells to both the drug and SARS-CoV-2 and then observe whether the drug’s presence served to hinder the virus’s efforts to infect cells,” explains Professor Watashi.
The researchers used this experimental system to screen a panel of drugs that are already approved for clinical use, including drugs like remdesivir and chloroquine that have already being approved or are being trialed as treatments for COVID-19.
In an exciting outcome, the researchers found two drugs that provided effective SARS-CoV-2 suppression: cepharanthine, which is used to treat inflammation, and nelfinavir, which is approved for the treatment of HIV infection.
Cepharanthine inhibited the entry of the virus into cells by preventing the virus from binding to a protein on the cell membrane, which it uses as a gateway. In contrast, nelfinavir worked to prevent the virus from replicating inside the cell by inhibiting a protein that the virus relies on for replication.
Given that these drugs have distinct antiviral mechanisms, using both of them together could be especially effective for patients, with computational models predicting that combined cepharanthine/nelfinavir therapy can hasten the clearance of SARS-CoV-2 from a patient’s lungs by as few as 4.9 days.
So, does this mean we will be seeing these new drugs in COVID-19 treatment centers?
Of course, the drug duo isn’t ready to be rolled out into healthcare systems just yet. These findings justify further research into the clinical potential of cepharanthine/nelfinavir therapy, and only following this can we say for sure that it is useful and helpful.
Nevertheless, given the ongoing nature of the COVID-19 pandemic and the ever-increasing death toll, the development of cepharanthine/nelfinavir therapy may provide clinicians and patients with a much-needed new treatment option.
Since the beginning of the COVID-19 pandemic, several strategies to face the virus have been engaged. One of them consists of drug repurposing. With this strategy, the emerge of marketed drugs with therapeutic potential for COVID-19 treatment has been suggested. Such is the case of cepharanthine, nelfinavir, and hydroxychloroquine.
Cepharanthine is a biscoclaurine alkaloid, currently used for radiation-induced leukopenia management, alopecia, idiopathic thrombocytopenic purpura, middle ear catarrh. It possesses anti-inflammatory, antioxidative, immunomodulating, and antiviral properties15.
Independent studies have demonstrated the potential use of cepharanthine for SARS-COV-2 treatment due to their potent antiviral activity16,17,18, which interferes with the Spike-ACE2 binding evading the viral entry to the host cells19, 20. Hydroxychloroquine is used to treat malaria, rheumatoid arthritis, chronic discoid lupus erythematosus, and systemic lupus erythematosus21.
In vitro antiviral properties against SARS-CoV-2 of hydroxychloroquine attract the attention, suggesting a possible role as a treatment for SARS-CoV-222. In this regard, hydroxychloroquine in vitro inhibitory activity was proven against SARS-CoV-2, with different mechanisms of action, such as sialic acid receptors blockade, cytokine storm prevention, endosomal pH elevation, and ACE-2 terminal glycosylation affectation leading to virus binding evasion23,24,25.
Currently, hydroxychloroquine is still being administered for COVID-19 treatment worldwide, but the clinical evidence of its therapeutic effectivity is still emerging; there is contradictory clinical evidence, some studies support the therapeutic efficacy while in others no significant improvements were observed26, 27.
Therefore, several studies are still being conducted at different levels for explaining hydroxychloroquine activity, one approach is the use of in silico studies, among them, the possible interaction of Hydroxychloroquine with Spike protein, specifically with RBD domain was suggested20, 28, 29.
Nelfinavir is currently used as an anti-HIV drug with protease inhibitor activity, several studies suggest that it inhibits SARS-CoV replication30, 31. Further, Musarrat et al., reported that it suppresses SARS-CoV-2 spike-mediated cell–cell fusion at micromolar ranges, besides molecular docking suggested that it might interact with HR1 region32.
reference link : https://www.nature.com/articles/s41598-021-84053-8
More information: Hirofumi Ohashi et al, Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment, iScience (2021). DOI: 10.1016/j.isci.2021.102367