Hydroxychloroquine Sulfate (Plaquenil): A Possible Candidate for Pandemic SARS-CoV-2 or (COVID-19)?

Hydroxychloroquine is a chloroquine derivative recognized for treating 'SARS-CoV-2 or COVID-19', among its other uses. It is one of the key drugs used for the treatment of malaria and other respiratory diseases. The drug exhibits multiple pharmacological activities such as anti-malarial, antidiabetic, anticancer, anti-HIV, antifungal, antimicrobial, and antioxidant activities. The coronavirus has recently shown five mutations or genetic change in its structure due to change in the climatic condition (i.e. R207C (nsp 2-27) - Wuhan (China), V378 I (nsp 2-198) - Italy, M2796I (nsp 4-33) - Iran, L3606F (nsp 6-37)-America and V9082F (ORF 7a-74) - Kuwait). There are many preclinical, clinical, theoretical, and experimental evidences that support the effectiveness of HCQ and CQ on patients affected by COVID-19. Based on the evidence currently underway and future research, we will be able to provide better analysis of the role of HCQ and CQ in the COVID-19 transition. It displays several activities related to the respiratory system, and numerous studies have suggested that the compound may be beneficial in protection against diseases such as malaria and lupus erythematosus. The present review represents the role and use of HCQ in the COVID-19 dis-ease. The object of this review study is based on the research evidence obtained from different au-thentic sources. It is currently used in the study of HCQ and CQ for the treatment of coronavirus and various other infections.Copyright © 2021 Bentham Science Publishers.

A systematic drug repurposing approach to identify promising inhibitors from FDA-approved drugs against Nsp4 protein of SARS-CoV-2.

COVID-19 is caused by SARS-CoV-2 and responsible for the ongoing global pandemic in the world. After more than a year, we are still in lurch to combat and control the situation. Therefore, new therapeutic options to control the ongoing COVID-19 are urgently in need. In our study, we found that nonstructural protein 4 (Nsp4) of SARS-CoV-2 could be a potential target for drug repurposing. Due to availability of only the crystal structure of C-terminal domain of Nsp4 (Ct-Nsp4) and its crucial participation in viral RNA synthesis, we have chosen Ct-Nsp4 as a target for screening the 1600 FDA-approved drugs using molecular docking. Top 102 drugs were found to have the binding energy equal or less than -7.0 kcal/mol. Eribulin and Suvorexant were identified as the two most promising drug molecules based on the docking score. The dynamics of Ct-Nsp4-drug binding was monitored using 100 ns molecular dynamics simulations. From binding free energy calculation over the simulation, both the drugs were found to have considerable binding energy. The present study has identified Eribulin and Suvorexant as promising drug candidates. This finding will be helpful to accelerate the drug discovery process against COVID-19 disease.Communicated by Ramaswamy H. Sarma.

WIDESPREAD OUTBREAK OF MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS IN A CAMEL COHORT AND ASSOCIATED SPILLOVER TO HUMANS IN KENYA

Background: Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that is endemic in dromedary camels. Kenya's >3 million camels have high seroprevalence of antibodies against MERS-CoV, with scant evidence of human infection, possibly due to a lower zoonotic potential of Clade C viruses, predominantly found in African camels. Methods: Between April 2018-March 2020, we followed camels aged 0-24 months from 33 camel-keeping homesteads within 50Km of Marsabit town through collecting deep nasal swabs and documenting signs of illness in camels every two weeks. Swabs were screened for MERS-CoV by reverse transcriptase (RT)-polymerase chain reaction (PCR) testing and virus isolation performed on PCR positive samples with cycle threshold (CT) <20. Both the isolates and swab samples (CT <30) were subjected to whole genome sequencing. Human camel handlers were also swabbed and screened for symptoms monthly and samples tested for MERS-CoV by RT-PCR. Results: Among 243 calves, 68 illnesses were recorded in 58 camels (53.9%);50/68 (73.5%) of illnesses were recorded in 2019, and 39 (57.3%) were respiratory symptoms (nasal discharge, hyperlacrimation and coughing). A total of 124/4,702 camel swabs (2.6%) from 83 (34.2%) calves in 15 (45.5%) enrolled compounds were positive for MERS-CoV RNA. Cases were detected between May-September 2019 with three infection peaks, a similar period when three (1.1%) human PCR-positive but asymptomatic cases were detected among 262 persons handling these herds. Sequencing of camel specimens revealed a Clade C2 virus with identical 12 nucleotide deletion at the 3' end of OFR3 region and one nucleotide insertion at the 5' region but lacked the signature ORF4b deletions of other Clade C viruses. Interpretation: We found high levels of transmission of distinct Clade C MERS-CoV among camels in Northern Kenya, with likely spillover infection to humans. These findings update our understanding of MERS-CoV epidemiology in this region.

Genetic and structure of novel coronavirus COVID-19 and molecular mechanisms in the pathogenicity of coronaviruses

The recently identified 2019 novel coronaviruses (2019-nCoV) has caused extra-human infections. 2019-nCoV identified a global threat that is causing an outbreak of unusual viral pneumonia in patients with severe acute respiratory syndrome (SARS)-coronaviruses 2 (SARS-CoV-2). Considering the relatively high identity of the receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homolog of the key regulator of blood pressure ACE. ACE2 also serves as the cellular entry point for the SARS virus, therefore, a prime target for pharmacological intervention. SARS-CoV-2 uses the SARS-CoV receptor for entry and the serine protease transmembrane protease serine 2 for spike (S) protein priming. That it is still necessary to develop novel mAbs that could bind specifically to 2019-nCoV RBD. Cell entry of coronaviruses depends on the binding of the viral S proteins to cellular receptors and S protein priming by host cell proteases. A transmembrane protease serine 2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention. This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats. We provide a brief introduction to the pathogenesis of SARS-CoV and Middle East respiratory syndrome-CoV and interaction between the RBD of coronavirus spike protein and ACE2.

Allogeneic, Off-the-Shelf, SARS-CoV-2-specific T Cells Demonstrate Reactivity Against Emerging Variant Strains

Background. The impact of COVID-19 has been profound with >170,000,000 confirmed cases worldwide and emerging variants being a cause of global concern. Defects in T-cell function and trafficking have been described among those with severe illness, and immunodeficiency is a risk factor for persistent viral shedding and prolonged symptoms. Because of our prior clinical data demonstrating that allogeneic, off-the-shelf virus-specific T cells (VSTs) can safely and effectively treat viral infections, we investigated the feasibility of targeting COVID-19 using banked, SARS-CoV-2-specific VSTs. Methods. We first screened PBMCs from convalescent individuals against 18 structural and non-structural/accessory (NSPs/APs) SARS-CoV-2 proteins and identified 5 [Spike (S), Membrane (M), Nucleoprotein (N), NSP4, and AP7a] as immunodominant which were then advanced to our VST production process. Results. Using overlapping peptide libraries spanning these antigens as a stimulus, we achieved a mean 7.6±0.9 fold expansion (n=13) of VSTs (96±0.5%), with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells that expressed activation and central/effector memory markers. These VSTs were potent, Th1-polarized and polyfunctional, producing IFNγ, TNFα, GM-CSF and Granzyme B. Moreover, the VSTs were able to kill pepmix-loaded autologous targets with no evidence of auto- or alloreactivity, attesting to their virus selectivity and safety for clinical use (Figure 1). Finally, though initially generated against the reference strain NC-045512.2 (Wuhan), these VSTs were able to recognize other clinically important variants including B1.1.7 (UK), B1.351 (South Africa) and P1 (Brazil). This demonstrates the cross-reactive potential of these polyclonal and diverse VSTs, which were developed to provide potent antiviral effects and minimize the risk of immune escape due to sequence variation. Figure 1: SARS-CoV-2 Specific T cells Have Demonstrated Selective Cytolytic Activity against SARS-CoV-2 While Leaving Non-Virus Infected Targets Intact. Conclusion. In conclusion, it is feasible to generate polyclonal SARS-CoV-2 VSTs that provide coverage against variant strains using GMP-compliant manufacturing methodologies. We have advanced this product to the bedside for administration in a Phase I, randomized clinical trial [VSTs+ standard of care (SOC) vs SOC] in high-risk patients hospitalized with COVID-19 (NCT04401410).