Current Pharmaceutical Design - Volume 27, Issue 33, 2021

The pandemic, well-known as COVID-19, has been caused by the coronavirus SARS-CoV-2 and it has distinct characteristics from other coronavirus-related epidemics. This pandemic has been ravaging the whole world for more than a year now, and no drugs or vaccines have been found to eliminate this virus from the infected people effectively; only physical measures like social distancing, hand washing and face-mask wearing have been taken to reduce its spread and very recently Veklury (remdesivir) has been permitted by the USFDA to manage the critical patients. This disease can be asymptomatic, but when it is symptomatic, it presents with respiratory problems and cold- or flu-like symptoms, which can be diagnosed with a chest CT and confirmed with RT-PCR tests. In this review, the taxonomy and structure of SARS-CoV-2 and history, transmission, epidemiology, pathology, clinical features and impacts of the COVID-19 have been discussed. A summary of possible drug targets, attempted physical and chemical measures, as well as vaccine candidates, has also been provided. How this coronavirus is different from other coronaviruses, the obstacles in managing this disease and the possibility of a second wave have also been reviewed. This review represents a wide range of information regarding COVID-19 and intends to be used as a comprehensive overview in this regard.

Today, the world is suffering from the pandemic of a novel coronavirus disease (COVID-19), a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the third fatal coronavirus outbreak that has already occurred in the 21st century. Even six months after its emergence, hundreds of thousands of people are still being infected with SARS-CoV-2, and thousands of lives are lost every day across the world. No effective therapy has been approved to date for the treatment of this disease, suggesting the need to broaden the scope in the search for effective treatments. Throughout history, folk medicine has been successfully used to treat various ailments in humans, and Traditional Chinese Medicine has been instrumental in the containment of a number of viral diseases. Owing to their high chemical diversity and safety profiles, natural products offer great promises as potentially effective antiviral drugs. In recent years, a large number of anti-coronaviral phytochemicals with different mechanisms of action have been identified. Among them, tetra-O-galloyl-β-D-glucose, caffeic acid, and saikosaponin B2 block viral entry. A number of flavonoids inhibit viral proteases. Silvestrol inhibits protein synthesis. Myricetin and scutellarein inhibit viral replication. Emodin, luteolin, and quercetin demonstrate anti-coronaviral activity by inhibiting multiple processes in the virus life cycle. In this review, we critically evaluate the findings of the natural product-based anticoronaviral research that has been published during the last two decades, and attempt to provide a comprehensive description about their utility as potential broad-spectrum anti-coronaviral drugs, examining leads that may guide/facilitate anti-SARS-CoV-2 drug development studies.

Coronavirus was first discovered during the year 1930 and since then, various coronaviruses like HKU1, MERS-CoV , NL63 and SARS-CoV-2 have been found to infect humans. The COVID-19 pandemic caused by SARS-CoV-2 is spreading at an alarming rate, thereby creating a health emergency around the world. SARS-CoV2 is reported to be originated from a wet animal market of Wuhan, China. Since then, the world is searching for effective ways to manage and treat the COVID-19 infection. The infections have already multiplied with several folds compared to the number of persons infected by Middle East Respiratory Syndrome Coronavirus and Severe Acute Respiratory Syndrome. In order to fill the gap of knowledge about this virus, several pieces of evidence are required to control it so more lives could be saved. The present review is based on the publicly available literature in order to explore the knowledge regarding epidemiology, virology, diagnosis, clinical features, pharmacological and therapeutic ways to treat the novel coronavirus. This can be helpful in offering novel insights and potential therapeutics for fighting this disease.

Background: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and re-emergence of human CoV outbreaks in the future. Methods: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design. Results: A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals’ handlers to the infected animals, environmental changes, improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable conditions for “host switching” and the emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide a potential “molecular switch” for preferences of new host-receptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs. Conclusion: High propensity of mutations and “molecular adaptations” in coronaviruses creates the hot spots and high potential for “host switching”, leading to the emergence of more virulent strains of human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for the emergence and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.

Background: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. Methods: The natural compounds library of Selleck Inc. (Catalog No. L1400) were retrieved from www.selleckchem.com. It contains 2230 compounds in sdf format, curated from natural sources. Prior to molecular docking, all the ligands were prepared by adding hydrogen atoms and merging them with non-polar hydrogen atoms. Gasteiger partial charges were added, rotatable bonds were defined, and the energies were minimized using MMFF94 forcefield (11,12). The three-dimensional coordinates of the main protease (Mpro), also known as 3C-like protein (3CLpro), was downloaded from the protein databank available at https://www.rcsb.org/structure/6LU7. The structure was solved to a resolution of 2.16 Å and is bound with a peptide-like inhibitor (N3)(8). The structure of target was prepared for molecular docking by adding hydrogen atoms, Kollman united atom type charges and solvation parameters using AutoDock Tool (ADT) (13). Results: We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (∼106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (∼104 M-1), and the reference drug Remdesivir (∼105 M-1). Conclusion: The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.