COVID 19 THERAPEUTICS STRATEGIES

Till date, no potential therapeutic agents (antivirals) have been discovered to treat specifically this Covid -19 global disease. Currently, researchers all over the world are working aggressively to discover a potential drug. Drug discovery and development is a tedious /challenging task, takes several years, and involves billions of dollars. Numerous experiments and techniques have been aimed at preventing further spread of COVID-19 and to improve successful and secure therapeutics. Depending on the target, possible anti-CoV therapies can be classified into two categories: (1) those acting on the Covid itself and (2) those acting on the human immune system or cells. The production of therapeutic methods is accelerated by elucidating immune responses caused by SARS-CoV-2.

Various pharmacological interventions have been implemented by countries to cure the disease, including currently proven antivirals, various oxygen therapy types, or mechanical ventilation. COVID-19 pandemic demands a rapid development of successful and efficacious therapeutics/pharmaceuticals that can be achieved through application of three principles: (i) the first approach includes investigating and testing the therapeutic efficacy of currently available antivirals. (ii) Molecular databases & repositories/libraries that can aid in high processing capacity and continuous evaluation of millions of potential therapeutics. (iii)Targeted treatment designed to interrupt the virus signalling (cellular and molecular pathways), and immunological response. The safest and easiest way to produce pharmaceutical products for treatment of SARS-CoV-2 is the first strategy, to find potential molecules from manufactured medicines. It may be accepted by the Green Channel or approved by the hospital ethics committee for accelerated clinical care of patients once effectiveness has been assessed. The approaches to drug repurposing can be performed by in vitro and in vivo studies using a conventional approach, or it can be achieved by a statistical approach, which relies on bioinformatics methods, ‘Big Data’ and ‘Artificial Intelligence’ (AI) to find new indications for drugs already in use, and subsequent validation in vitro and in vivo.

Broad-spectrum antivirals, such as IFNs, ribavirin, and cyclophilin inhibitors have been used to treat Covid pneumonia. The benefit of these therapies is that, since they have been approved for the treatment of other viral infections, their metabolic properties, dosages used, possible effectiveness and side effects are known. However, because these therapies are broad-spectrum, they are unable to directly kill Covid and potential side effects should be considered. Unfortunately, due to differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties, in vitro analysis seldom translates to in vivo, posing a significant barrier to clinical translation of a therapeutic candidate. Already approved pharmaceuticals, including antimalarials, antiviral, lysosomotropic drugs; and then selected broad spectrum antibiotics, & immunotherapeutic drugs, are the key classes of therapeutic agents that seem effective in COVID-19 therapy and are currently being recommended in various countries.

Ribavirin is used in the management of many viral infections, including chronic hepatitis C virus, viral hemorrhagic fever and respiratory syncytial virus, in conjunction with other antiviral medications and, in certain instances, Interferons-Alpha(IFN-a). Ribavirin was first commercialized in the early 1980s for the treatment of respiratory syncytial virus in infants, making it the most well-known and widely used antiviral agent. Aside from being regarded as a broad-spectrum antiviral agent against DNA and RNA, which can obstruct viral messenger RNA binding RNA-dependent RNA polymerase production (RpRd), it is also a prodrug that metabolizes into nucleoside analogues that block viral RNA and capping viral mRNA. The combination of nitazoxanide, ribavirin, and ivermectin, as well as zinc supplementation, removed SARS-CoV-2 from the nasopharynx faster than symptomatic treatment.

Remdesivir is one of the most effective antiviral medicines for managing coronavirus infection that has been studied. It is an adenosine nucleotide phosphoramidite prodrug with broad- spectrum in-vitro antiviral activity against a variety of RNA viruses. Remdesivir, while being a nucleotide precursor, has been shown to prevent viral RNA replication and to prematurely terminate viral RNA transcription by targeting viral RNA- dependent RNA polymerase. For individuals at high risk of hyper-inflammation who are diagnosed early during illness (≤10 days) and require supplemental oxygen, the Remdesivir therapy reduced the period to rehabilitation by four days, which is significant improvement for patients and healthcare systems. However, for patients with mild or moderately severe COVID-19 and no need for respiratory support, Remdesivir does not offer significant benefit at day 28. Therefore, Remdesivir is considered as an important COVID-19 treatment option only in selected patient.

Ivermectin is an anti-parasitic broad-spectrum drug that has been shown to prevent HIV-1 replication. In-vitro analysis performed in Australia, Ivermectin’s antiviral activity on SARS-CoV-2 infected cells showed a 93 percent reduction in viral RNA present in the supernatant and a 99.80 percent reduction in cell-associated viral RNA. A randomized, double-blind, placebo-controlled study of adult SARS-CoV-2 patients revealed that adult patients with mild COVID-19 treated with 12mg of Ivermectin resulted in an earlier clearance of the virus with a 5-day course. The treatment was found to be both safe and successful. However, to validate these preliminary results, larger studies would be needed.

Interestingly, plant based natural products such as plant metabolites are also extensively in use to fight Covid infection. Furthermore, various research groups revealed that lipid metabolism, RNA-dependent RNA polymerase, many virus structural proteins can act as potential drug targets for the management of COVID-19. However, clinical trials are undergoing to screen and translate a potential therapeutic candidate for the management of COVID-19.

The technique of high-throughput screening, which for instance, contributed to the discovery of the anti-HIV infection drug lopinavir/ritonavir, may identify many drug molecules. Through a strategy focused on genomic knowledge and pathological characteristics of various Covids, the drugs detected would show stronger anti-Covid effects, but the new drug discovery phase could take many years or even more than 10 years to complete.