Dr. Mandeep Kour
We are facing a global highly pathogenic novel coronavirus (SARS-CoV-2) that has already infected more than 12.2 million people and caused more than 5 lac deaths worldwide. SARS-CoV-2 belongs to Beta coronavirus together with two highly pathogenic viruses, SARS-CoV and MERS-CoV. SARS-CoV-2 is a single-stranded positive-sense RNA genome encapsulated within a membrane envelope. The viral membrane is studded with glycoprotein spikes that give coronaviruses their crown like appearance. Similarly to SARS-CoV and MERS-CoV, SARS-CoV-2 attacks the lower respiratory system to cause viral pneumonia, but it may also affect the gastrointestinal system, heart, kidney, liver, and central nervous system leading to multiple organ failure. SARS-CoV-2 is more transmissible/contagious than SARS-CoV. To control this pandemic several drugs, such as favipiravir, remdesivir, umifenovir, lopinavir/ ritonavir, darunavir, sarilumab, chloroquine and hydroxychloroquine are currently undergoing clinical trials to test their efficacy and safety in the treatment of COVID-19.
Favipiravir (Avigan, T-705)
Favipiravir (Avigan) also known as T-705 was first approved for treatment of influenza virus and is the inhibitor of RNA-dependent RNA polymerase (RdRp) in RNA viruses such as SARS-CoV-2. Favipiravir was first developed in Japan by Fujifilm Toyama chemical company and is licensed in Japan and China. It selectively inhibits RNA-dependent RNA polymerase (RdRp), an enzyme needed for RNA viral replication with in human cells. It functions as a purine analogue and is incorporated instead of guanine and adenine. The incorporation of a single molecule of favipiravir terminates the elongation of viral RNA. It has a broad spectrum of activity towards RNAviruses (Influenza, Rhino and Respiratory Syncytial virus etc.) but not against DNA viruses. With regard to its mechanism, it is reported that favipiravir antagonizes viral RNA synthesis by acting as a chain terminator at the site where the RNA is incorporated into the host cell. By contrast, oseltamivir (Tamiflu), a neuraminidase inhibitor, blocks the cleavage of sialic acid and the subsequent entry of the virus into the cell. Importantly, favipiravir, unlike oseltamivir, does not seem to generate resistant viruses. This property of favipiravir suggests a potential benefit in the treatment of COVID-19. CSIR- IIIM, Jammu and Anphar laboratories Pvt. Ltd have jointly developed synthetic lab process of Favipiravir. This project was undertaken jointly by IIIM and Anphar Laboratories Pvt. Ltd immediately after the first lockdown was announced. The most important achievement of this project is that not even a single chemical/raw material is imported thus objectives of Aatamnirbharta is accomplished in this case.
Remdesivir (GS-5734)
Remdesivir is a nucleotide analog that is used for the treatment of infections caused by the Ebola virus and the Marburg virus but now is among the front runners for the therapy of novel corona virus, SARS-CoV-2. Remdesivir was invented by Gilead Sciences and had shown broad spectrum of activity against RNA viruses. Remdesivir resembles the RNA base adenosine and has several important features in its structure making it a strong inhibitor of viral RNA polymerase. It resembles the RNA building block and is taken up by the virus into its RNA strands causing chain termination. It is therefore one of the most promising compounds for treating COVID-19.
Umifenovir (Arbidol)
Umifenovir (arbidol) was first invented by Pharmstandard and has shown efficacy in the treatment of influenza virus infection. It is claimed to be a viral entry inhibitor to the target cells. Interestingly, it does not have significant side effects and is patented for the treatment of SARS infection. It has shown very promising activity against SARS-CoV-2 in vitro showing inhibition of the virus at concentration as low as 10-30 ?M.
Lopinavir/ ritonavir
Lopinavir is an antiretroviral drug which inhibits the protease enzyme and can be formulated together with another protease inhibitor ritonavir which decreases the metabolism of the former by inhibiting the cytochrome (CYT) P4503A enzyme. Lopinavir/ritonavir drugs combination (Kaletra) was approved for the treatment of HIV and was found to have in vitro anti-SARS-CoV efficacy. However, Kaltera can be useful in the early stages of the SARS-CoV-2 infection and might be beneficial for the milder disease conditions and a multi-country clinical trial is to be conducted for this combination.
Darunavir
Darunavir (Prezista) is another antiviral drug used as HIV-1 protease inhibitor that was shown to have promising anti-SARS-CoV-2 activity in vitro. It was shown to inhibit the viral replication at a concentration of 300 M. However, Johnson and Johnson announced on March 18, 2020 that there is no any evidence to support the activity of darunavir against SARS-CoV-2.
Sarilumab
Sarilumab (Kevzara) is a human monoclonal antibody against the interleukin-6 (IL-6) receptor. As IL-6 is the host target for SARS-CoV-2, its activation could result in severe respiratory symptoms due to lung inflammation. Sarilumab was first developed by Regeneron Pharmaceuticals Inc., US and has collaborated with Sanofi has announced on March 16 to conduct phase II/III clinical trials for the evaluation of Kevzara in around 400 patients hospitalized with COVID-19 infection. It is expected to reduce the overactive inflammatory response of the lungs by blocking the IL-6 receptor. These trials would be conducted to test the efficacy and safety of sarilumab and remdesivir which is the investigational new drug.
Chloroquine (CQ) and hydroxychloroquine (HCQ)
Chloroquine (CQ) and hydroxychloroquine (HCQ) are aminoquinolines, which have been used to treat malaria and autoimmune diseases for over 50 years. CQ which has been used since 1934, has several anti-inflammatory and antiviral effects that have been reported by previous studies. HCQ sulfate, a derivative of CQ, was first synthesized in 1946 by introducing a hydroxyl group into CQ and was demonstrated to be much less (~40%) toxic than CQ in animals. More importantly, HCQ is still widely available to treat autoimmune diseases, such as systemic lupus erythematous and rheumatoid arthritis. Since CQ and HCQ share similar chemical structures and mechanisms of acting as a weak base and immunomodulation, it is easy to conjure up the idea that HCQ may be a potent candidate to treat infection by SARS-CoV-2.
Besides their antimalarial effects, these two drugs possess immunomodulation effects allowing them to use for the treatment of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis. HCQ and CQ can inhibit certain cellular functions and molecular pathways involved in immune activation partly by accumulating in lysosomes and auto phagosomes of phagocytic cells and changing local pH concentrations.
A number of ways to combat the corona virus infection which include development of vaccine develop a new drug that could target the virus or the host cell, but again this would take several years and we can’t wait for that long. A new drug takes at least 14 years to get introduced to the market from the research and development phase and this remains an unlikely solution for this major problem. The other and most likely way to control the corona virus pandemic is to test the SARS-CoV-2 using existing drugs as most of the viruses share similar genome. In an attempt to treat the corona virus using this method, a number of different antiviral and other drugs are used and fortunately few drugs have shown a ray of hope as far as the reduction in duration of therapy and viral load is concerned.
A number of trials have been conducted to come up with a drug which shows significant efficacy and safety in the treatment of COVID-19. Few have shown encouraging results and few are in pipeline. The Indian council of medical research (ICMR) has also started clinical trials on the effectiveness of Remdesivir, Chloroquine /Hydroxychloroquine, Lopinavir/ Ritonavir and Lopinavir/Ritonavir with interferon (Bla) as a anti-viral drugs against COVID-19 as a part of WHO solidarity trial. Hopefully, we would be able to identify the most suitable approach to fight this deadly virus very soon and make this world a healthy place to live again.
(The author is Post-Doctoral Researcher in Medicinal chemistry, CSIR-IIIM Jammu)
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