Evaluation of the active constituents of Nilavembu Kudineer for viral replication inhibition against SARS‐CoV‐2: An approach to targeting RNA‐dependent RNA polymerase (RdRp)

The World Health Organization has declared the novel coronavirus (COVID‐19) outbreak a global pandemic and emerging threat to people in the 21st century. SARS‐CoV‐2 constitutes RNA‐Dependent RNA Polymerase (RdRp) viral proteins, a critical target in the viral replication process. No FDA‐approved drug is currently available, and there is a high demand for therapeutic strategies against COVID‐19. In search of the anti‐COVID‐19 compound from traditional medicine, we evaluated the active moieties from Nilavembu Kudineer (NK), a poly‐herbal Siddha formulation recommended by AYUSH against COVID‐19. We conducted a preliminary docking analysis of 355 phytochemicals (retrieved from PubChem and IMPPAT databases) present in NK against RdRp viral protein (PDB ID: 7B3B) using COVID‐19 Docking Server and further with AutoDockTool‐1.5.6. MD simulation studies confirmed that Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) revealed better binding activity against RdRp (PDB ID: 7B3B) in comparison with Remdesivir. The study suggests a potential scaffold for developing drug candidates against COVID‐19. PRACTICAL APPLICATIONS: Nilavembu Kudineer is a poly‐herbal Siddha formulation effective against various diseases like cough, fever, breathing problems, etc. This study shows that different phytoconstituents identified from Nilavembu Kudineer were subjected to in silico and ADME analyses. Out of the former 355 phytochemical molecules, Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) showed better binding activity against RdRp viral protein (PDB ID: 7B3B) in comparison with the synthetic repurposed drug. Our work explores the search for an anti‐COVID‐19 compound from traditional medicine like Nilavembu Kudineer, which can be a potential scaffold for developing drug candidates against COVID‐19.

Advancements in COVID- 19 Testing: An in-depth overview.

COVID-19 rapidly evolved as a pandemic, killing and hospitalising millions of people, creating unprecedented hurdles for communities and health care systems worldwide. The rapidly evolving pandemic prompted the head of the World Health Organisation to deliver a critical message: "test, test, test." The response from the diagnostic industry and researchers worldwide was overwhelming, resulting in more than a thousand commercial tests available in the market worldwide. Several sampling approaches and diagnostic techniques have been employed from the early stages of the pandemic, such as SARS-CoV-2 detection by targeting the viral RNA or protein, indirectly via antibody testing, biochemical estimation, and various imaging techniques, and many are still in the various stages of development and yet to be marketed. Accurate testing techniques and appropriate sampling are the need of the hour to manage, diagnose and treat the pandemic, especially in the current crisis, where SARS-CoV-2 undergoes constant mutation, evolving into various strains, which are pretty challenging. The article discusses various testing techniques as well as screening methods for detection, treatment, and management of COVID-19 transmission, such as NAAT, PCR, isothermal detection including RT-LAMP, RPA, NASBA, RCA, SDA, NEAR, and TMA, CRISPR strategy, nanotechnology approach, metagenomic profiling, point of care tests, virus neutralization test, ELISA, biomarker estimation, utilization of imaging techniques such as CT, ultrasonography, brain MRI in COVID-19 complications, and other novel strategies including microarray methods, microfluidic methods and artificial intelligence with an emphasis on advancements in the testing strategies for the diagnosis, management, and prevention of COVID-19.

Evaluation of the active constituents of Nilavembu Kudineer for viral replication inhibition against SARS-CoV-2: An approach to targeting RNA-dependent RNA polymerase (RdRp).

The World Health Organization has declared the novel coronavirus (COVID-19) outbreak a global pandemic and emerging threat to people in the 21st century. SARS-CoV-2 constitutes RNA-Dependent RNA Polymerase (RdRp) viral proteins, a critical target in the viral replication process. No FDA-approved drug is currently available, and there is a high demand for therapeutic strategies against COVID-19. In search of the anti-COVID-19 compound from traditional medicine, we evaluated the active moieties from Nilavembu Kudineer (NK), a poly-herbal Siddha formulation recommended by AYUSH against COVID-19. We conducted a preliminary docking analysis of 355 phytochemicals (retrieved from PubChem and IMPPAT databases) present in NK against RdRp viral protein (PDB ID: 7B3B) using COVID-19 Docking Server and further with AutoDockTool-1.5.6. MD simulation studies confirmed that Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) revealed better binding activity against RdRp (PDB ID: 7B3B) in comparison with Remdesivir. The study suggests a potential scaffold for developing drug candidates against COVID-19. PRACTICAL APPLICATIONS: Nilavembu Kudineer is a poly-herbal Siddha formulation effective against various diseases like cough, fever, breathing problems, etc. This study shows that different phytoconstituents identified from Nilavembu Kudineer were subjected to in silico and ADME analyses. Out of the former 355 phytochemical molecules, Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) showed better binding activity against RdRp viral protein (PDB ID: 7B3B) in comparison with the synthetic repurposed drug. Our work explores the search for an anti-COVID-19 compound from traditional medicine like Nilavembu Kudineer, which can be a potential scaffold for developing drug candidates against COVID-19.

FDA-Approved Trifluoromethyl Group-Containing Drugs: A Review of 20 Years

As people around the world regard 2020 as the year of COVID-19, the medical community considers this year to be the second-best year, shared with the year 1996, with respect to the number of drug molecules approved by the US Food and Drug Administration (FDA). Both years, 2020 and 1996, had a record of 53 new drug molecules approved by the FDA. In the year 2020, 53 new chemical entities and 13 biological medicines were approved, including 10 monoclonal antibodies, 2 antibody-drug conjugates, 3 peptides, and 2 oligonucleotides. Among them, most of the compounds were found to have fluorine or fluorine-containing functional groups exhibiting numerous pharmacological activities. Herein, we summarized the trifluoromethyl (TFM, -CF3)-group-containing FDA-approved drugs for the last 20 years. This article specially features and details the previous 20-year literature data, covering CF3-incorporated potential drug molecules, including their syntheses and uses for various diseases and disorders. The review covers the detailed chemistry of 19 FDA-approved drugs in the past 20 years, which contains the TFM group as one of the pharmacophores.

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

Critical role of nitric oxide in impeding COVID-19 transmission and prevention: a promising possibility.

COVID-19 is a serious respiratory infection caused by a beta-coronavirus that is closely linked to SARS. Hypoxemia is a symptom of infection, which is accompanied by acute respiratory distress syndrome (ARDS). Augmenting supplementary oxygen may not always improve oxygen saturation; reversing hypoxemia in COVID-19 necessitates sophisticated means to promote oxygen transfer from alveoli to blood. Inhaled nitric oxide (iNO) has been shown to inhibit the multiplication of the respiratory coronavirus, a property that distinguishes it from other vasodilators. These findings imply that NO may have a crucial role in the therapy of COVID-19, indicating research into optimal methods to restore pulmonary physiology. According to clinical and experimental data, NO is a selective vasodilator proven to restore oxygenation by helping to normalize shunts and ventilation/perfusion mismatches. This study examines the role of NO in COVID-19 in terms of its specific physiological and biochemical properties, as well as the possibility of using inhaled NO as a standard therapy. We have also discussed how NO could be used to prevent and cure COVID-19, in addition to the limitations of NO.

Anticipated pharmacological role of Aviptadil on COVID-19.

Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS-Cov-2 was found responsible for the disease COVID-19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID-19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil's benefit. However, such drugs like Aviptadil in COVID-19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds.

Nanotechnology-based Approaches and Investigational Therapeutics against COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus responsible for the current global pandemic, which first emerged in December 2019. This coronavirus has affected 217 countries worldwide, most of which have enacted non-remedial preventive measures, such as nationwide lockdowns, work from home, travel bans, and social isolation. Pharmacists, doctors, nurses, technologists, and other healthcare professionals have played pivotal roles during this pandemic. Unfortunately, confirmed drugs have not been identified for the treatment of patients with coronavirus disease 2019 (COVID-19) caused by SARSCoV2; however, favipiravir and remdesivir have been reported as promising antiviral drugs. Some vaccines have already been developed, and vaccination is ongoing globally. Various nanotechnologies are currently being developed in many countries for preventing SARS-CoV-2 spread and treating COVID-19 infections. In this article, we present an overview of the COVID-19 pandemic situation and discuss nanotechnology-based approaches and investigational therapeutics for COVID-19.

Current Perspective of COVID-19 on Neurology: A Mechanistic Insight.

SARS-CoV-2, the novel coronavirus and the causative organism of the Covid-19 pandemic wreaked havoc worldwide producing asymptomatic to symptomatic cases leading to significant morbidity and mortality even after infection. Most of the countries reported a mortality rate of 2-3 % majorly due to cardiorespiratory failures. Recent studies highlighted the neurological involvement playing a key role in cardiorespiratory failures and other symptoms such as headache, anosmia, and ageusia observed in Covid-19 patients. Studies suggest SARS-CoV-2 entry via Olfactory Epithelium (OE), and the expression of type 2 transmembrane serine protease (TMPRSS2) in addition to Angiotensin-Converting Enzyme 2 (ACE2) can facilitate SARS-CoV-2 neurotropism. The virus can either travel via peripheral blood vessel causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction or reach the systemic circulation and take a different route to the Blood-Brain Barrier (BBB), disrupting the BBB causing neuroinflammation or neuronal excitotoxicity resulting in the development of encephalitis, encephalopathy, seizures, and strokes. SARS-CoV-2 invasion on the brain stem is believed to be responsible for the cardiorespiratory failures observed in Covid-19 patients. Apart from viral invasion via hematogenous route, SARS-CoV-2 neural invasion via PNS nerve terminal, results in viral replication and retrograde transportation to soma leading to invasion of the CNS including the brain producing neurological manifestations of the disease either in the initial stages or during the course of the disease and even for a long period post-infection in many cases. The ACE2 receptors are expressed in the brain and glial cells and SARS-CoV-2 acts via neuronal as well as nonneuronal pathways. But the exact cell types involved and how they can trigger inflammatory pathways need further in-depth study for the development of targeted therapy.

COVID-19 and Domestic Animals: Exploring the Species Barrier Crossing, Zoonotic and Reverse Zoonotic Transmission of SARS-CoV-2.

BACKGROUND: To date, more than thirty animals have been tested positive for SARS-CoV-2; all of them infected by humans with COVID-19. Some animal experiments suggested the possibility of animal to animal transmission of SARS-CoV-2 that was seen in some cases of infected animals. Animal to human transmission was considered unlikely until investigations revealed the possibility of mink to human transmission of SARS-CoV-2 in the Netherlands. OBJECTIVE: The current study aims at highlighting the predominance of SARS-CoV-2 infection in various animal species, reverse zoonotic transmission and proposing possible animal models that might aid in the study and development of a vaccine against Covid-19. METHODS: The authors have gathered information on various animal species infected with SARS-CoV-2 and possible tests conducted via online news reports, websites and Scopus indexed journals. RESULTS: The study of the susceptibility of SARS-CoV-2 to domestic animals concluded that pigs, chicken, and ducks were not vulnerable to Covid-19; dogs showed less susceptibility to SARS-CoV-2 and cats as well as ferrets were seen susceptible to Covid-19. SARS-CoV-2 has been seen crossing the species barrier, infecting humans from the wild with the yet unclear source, spreading from humans to humans quickly, humans to animals, animals to animals, and is likely to spread from animals to humans even though minimally. Animals appear somewhat resistant to SARS-CoV-2 transmission compared to humans who globally crossed eight million infection cases, and the infected animals mostly do not show many complications and recover quickly. CONCLUSION: Precautions are advised to prevent human to animal transmission of the virus, and in some areas, to avoid animal to human spread of the virus. Further monitoring is required to assess the SARS-CoV-2 infection in animals as COVID-19 is a rapidly evolving condition worldwide. Cats and ferrets have physiological resemblance and genome sequencing studies propose the possibility of these species to be used as animal models for investigating the SARS-CoV-2 infection and this might aid in further studies and vaccine development against Covid-19.

Natural Products Database Screening for the Discovery of Naturally Occurring SARS-Cov-2 Spike Glycoprotein Blockers.

SARS-CoV-2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best-in-class derivatives in silico able to target an essential structure of the virus and to act in the early stage of infection.

The Chronicle of COVID-19 and Possible Strategies to Curb the Pandemic.

COVID-19, a type of infection that emerged in Wuhan, has become a pandemic affecting people worldwide and is rapidly spreading and evolving. Day by day, the confirmed cases and deaths are increasing many folds. SARS-CoV-2 is a novel virus; therefore, limited data are available to curb the disease. Epidemiological approaches, such as isolation, quarantine, social distancing, lockdown, and curfew, are being employed to halt the spread of the disease. Individual and joint efforts all over the world are producing a wealth of data and information which are expected to produce therapeutic strategies against COVID-19. Current research focuses on the utilization of antiviral drugs, repurposing strategies, vaccine development, as well as basic to advanced research about the organism and the infection. The review focuses on its life cycle, targets, and possible therapeutic strategies, which can lead to further research and development of COVID-19 therapy.