Plant derived active compounds as potential anti SARS-CoV-2 agents: an in-silico study.

Plants are a valued potential source of drugs for a variety of diseases and are often considered less toxic to humans. We investigated antiviral compounds that may potentially target SARS-CoV-2 antigenic spike (S) and host proteins; angiotensin-converting enzyme2 (ACE2), and transmembrane serine protease2 (TMPRSS2). We scrutinized 36 phytochemicals from 15 Indian medicinal plants known to be effective against RNA viruses via molecular docking. Besides, the TMPRSS2 structure was modeled and validated using the SWISS-MODEL. Docking was performed using Autodock Vina and 4.2 followed by visualization of the docking poses on Pymol version 2.4.0 and Discovery Studio Visualizer. Molecular docking showed that 12 out of 36 active compounds interacted efficiently with S, ACE2, and TMPRSS2 proteins. The ADMET profile generated using the swissADME and pkCSM server revealed that these compounds were possessed druggable properties. The Amber 12 simulation package was used to carry out energy minimizations and molecular dynamics (MD) simulations. The total simulation time for both S protein: WFA and S protein: WND complexes was 300 ns (100 ns per replica). A total of 120 structures were extracted from the last 60 ns of each MD simulation for further analysis. MM-PBSA and MM-GBSA were employed to assess the binding energy of each ligand and the receptor-binding domain of the viral S-protein. The methods suggested that WND and WFA showed thermodynamically favorable binding energies, and the S protein had a higher affinity with WND. Interestingly, Leu455 hotspot residue in the S protein, also predicted to participate in binding with ACE2, was engaged by WND and WFA. HighlightsPlants' natural active compounds may aid in the development of COVID-19 therapeutics.MD simulation study revealed stable binding of withanolide D and withaferin A with spike proteinWithanolide D and withaferin A could be effective against SARS-CoV-2 spike protein.Discovery of druggable agents that have less or lack of binding affinity with ACE2 to avoid the organs associated with comorbidities.According to ADMET selected phytochemicals may be used as druggable compounds.Communicated by Ramaswamy H. Sarma.

Redefining Lobe-Wise Ground-Glass Opacity in COVID-19 Through Deep Learning and its Correlation With Biochemical Parameters.

During COVID-19 pandemic qRT-PCR, CT scans and biochemical parameters were studied to understand the patients' physiological changes and disease progression. There is a lack of clear understanding of the correlation of lung inflammation with biochemical parameters available. Among the 1136 patients studied, C-reactive-protein (CRP) is the most critical parameter for classifying symptomatic and asymptomatic groups. Elevated CRP is corroborated with increased D-dimer, Gamma-glutamyl-transferase (GGT), and urea levels in COVID-19 patients. To overcome the limitations of manual chest CT scoring system, we segmented the lungs and detected ground-glass-opacity (GGO) in specific lobes from 2D CT images by 2D U-Net-based deep learning (DL) approach. Our method shows accuracy, compared to the manual method (  âˆ¼ 80%), which is subjected to the radiologist's experience. We determined a positive correlation of GGO in the right upper-middle (0.34) and lower (0.26) lobe with D-dimer. However, a modest correlation was observed with CRP, ferritin and other studied parameters. The final Dice Coefficient (or the F1 score) and Intersection-Over-Union for testing accuracy are 95.44% and 91.95%, respectively. This study can help reduce the burden and manual bias besides increasing the accuracy of GGO scoring. Further study on geographically diverse large populations may help to understand the association of the biochemical parameters and pattern of GGO in lung lobes with different SARS-CoV-2 Variants of Concern's disease pathogenesis in these populations.

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.

A comparative analysis of COVID-19 outbreak on age groups and both the sexes of population from India and other countries.

INTRODUCTION: The study of epidemiological outcomes of COVID-19 in the affected countries needs to be conducted to implement an effective strategy. METHODOLOGY: Our study included age and sex-based analysis of epidemiological data of infected and deceased patients from various countries. The patient data was graphically depicted with the slope's calculation to describe a gradual or steep spread of the disease along with subsequent rise or fall in the death reports. RESULTS: Population groups of 20-49 years of age and 50 years-above were highly vulnerable to infection. Interestingly, 20-49 years of age group was most affected in India. However, higher population of the deceased were reported in the 50 years-above in all countries. India and South Korea demonstrated a gradual appearance of COVID-19 positive cases than other countries illustrated by reduced slope %. Further the highest percentage of infected people and deaths were reported from the densely populated states of India. We observed a sex independent prevalence of COVID-19. The BCG and JE vaccine are unique in the vaccination regime of India and South Korea. CONCLUSIONS: Reduced ACE-2 expression in the children's nasal epithelium may be responsible for reduced SARS-CoV-2 susceptibility. Countries showed varying patterns in COVID-19 spread and associated mortality. It may be influenced by factors, such as screening strategy, countries demography, implementation of lockdown, etc. Due to limited evidence, it would be difficult to point to the influence of the virus on either sexes. Although vaccines may stimulate non-specific immunity, experimental proofs are needed to demonstrate the potential of any vaccine against SARS-CoV-2.

An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.

Mutational analysis of structural proteins of SARS-CoV-2.

SARS-CoV-2 transmissibility is higher than that of other human coronaviruses; therefore, it poses a threat to the populated communities. We investigated mutations among envelope (E), membrane (M), and spike (S) proteins from different isolates of SARS-CoV-2 and plausible signaling influenced by mutated virus in a host. We procured updated protein sequences from the NCBI virus database. Mutations were analyzed in the retrieved sequences of the viral proteins through multiple sequence alignment. Additionally, the data was subjected to ScanPROSITE to analyse if the mutations generated a relevant sequence for host signaling. Unique mutations in E, M, and S proteins resulted in modification sites like PKC phosphorylation and N-myristoylation sites. Based on structural analysis, our study revealed that the D614G mutation in the S protein diminished the interaction with T859 and K854 of adjacent chains. Moreover, the S protein of SARS-CoV-2 consists of an Arg-Gly-Asp (RGD) tripeptide sequence, which could potentially interact with various members of integrin family receptors. RGD sequence in S protein might aid in the initial virus attachment. We speculated crucial host pathways which the mutated isolates of SARS-CoV-2 may alter like PKC, Src, and integrin mediated signaling pathways. PKC signaling is known to influence the caveosome/raft pathway which is critical for virus entry. Additionally, the myristoylated proteins might activate NF-κB, a master molecule of inflammation. Thus the mutations may contribute to the disease pathogenesis and distinct lung pathophysiological changes. Further the frequently occurring mutations in the protein can be studied for possible therapeutic interventions.

A review of the presence of SARS-CoV-2 RNA in wastewater and airborne particulates and its use for virus spreading surveillance.

According to the WHO, on October 16, 2020, the spreading of the SARS-CoV-2, responsible for the COVID-19 pandemic, reached 235 countries and territories, and resulting in more than 39 million confirmed cases and 1.09 million deaths globally. Monitoring of the virus outbreak is one of the main activities pursued to limiting the number of infected people and decreasing the number of deaths that have caused high pressure on the health care, social, and economic systems of different countries. Wastewater based epidemiology (WBE), already adopted for the surveillance of life style and health conditions of communities, shows interesting features for the monitoring of the COVID-19 diffusion. Together with wastewater, the analysis of airborne particles has been recently suggested as another useful tool for detecting the presence of SARS-CoV-2 in given areas. The present review reports the status of research currently performed concerning the monitoring of SARS-CoV-2 spreading by WBE and airborne particles. The former have been more investigated, whereas the latter is still at a very early stage, with a limited number of very recent studies. Nevertheless, the main results highlights in both cases necessitate more research activity for better understating and defining the biomarkers and the related sampling and analysis procedures to be used for this important aim.

Recent updates on COVID-19: A holistic review.

Coronaviruses are large positive-sense RNA viruses with spike-like peplomers on their surface. The Coronaviridae family's strains infect different animals and are popularly associated with several outbreaks, namely SARS and MERS epidemic. COVID-19 is one such recent outbreak caused by SARS-CoV-2 identified first in Wuhan, China. COVID-19 was declared a pandemic by WHO on 11th March 2020. Our review provides information covering various facets of the disease starting from its origin, transmission, mutations in the virus to pathophysiological changes in the host upon infection followed by diagnostics and possible therapeutics available to tackle the situation. We have highlighted the zoonotic origin of SARS-CoV-2, known to share 96.2% nucleotide similarity with bat coronavirus. Notably, several mutations in SARS-CoV-2 spike protein, nucleocapsid protein, PLpro, and ORF3a are reported across the globe. These mutations could alter the usual receptor binding function, fusion process with the host cell, virus replication, and the virus's assembly. Therefore, studying these mutations could help understand the virus's virulence properties and design suitable therapeutics. Moreover, the aggravated immune response to COVID-19 can be fatal. Hypertension, diabetes, and cardiovascular diseases are comorbidities substantially associated with SARS-CoV-2 infection. The review article discusses these aspects, stating the importance of various comorbidities in disease outcomes. Furthermore, medications' unavailability compels the clinicians to opt for atypical drugs like remdesivir, chloroquine, etc. The current diagnostics of COVID-19 include qRT-PCR, CT scan, serological tests, etc. We have described these aspects to expose the information to the scientific community and to accelerate the research.

SARS-CoV-2, an Underestimated Pathogen of the Nervous System.

Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Additionally, transmembrane serine protease 2 (TMPRSS2) and furin facilitate virus entry into the host. Besides, the probable routes of virus entry into the nervous system include the hematogenic pathway, through the vagus, the olfactory nerve, or the enteric nervous system. However, the trajectory of SARS-CoV-2 to the brain needs investigation. Furthermore, a Th17-mediated cytokine storm is seen in COVID-19 cases with higher levels of IL-1ß/2/7/8/9/10/17, GM-CSF, IFN-γ, TNF-α, CXCL-10, MCP1, and MIP1α/ß. Some cytokines can cross the blood-brain barrier and activate the brain's immune cells to produce neural cytokines, leading to neuronal dysfunctions. Nonetheless, most of the neurological conditions developed due to viral infections may not have effective and registered treatments. Although, some antivirals may inhibit the virus-mediated pathogenesis and prove to be suitable in COVID-19 treatment. Therefore, clinicians' and researchers' collective expertise may unravel the potential of SARS-CoV-2 infection to prevent short-term and long-term CNS damage.

Comorbidity Assessment Is Essential During COVID-19 Treatment.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV2 is associated with various comorbidities; cardiovascular diseases, hypertension, diabetes, liver, lung diseases, and neurological ailments. The majority of the dysfunctions mentioned above are often associated with endothelial deterioration, indicating that endothelium can be the target of SARS-CoV2. Our study is an exclusive observational study that quantitatively analyses COVID-19 related comorbidities. We retrieved the data of % population of COVID-19 hospitalized and deceased patients with associated comorbidities from publicly accessible portals of the five European countries. A two tailed t-test enabled us to determine the significant proportions of deaths compared to hospitalized patients with associated comorbidity. Our study revealed that deaths associated with cardiovascular diseases and diabetes are highly significant (p < 0.0001) compared to hospitalized in countries like Italy, France, and Spain unlike the Netherlands. Deaths from kidney diseases (Italy- p < 0.0001; Sweden- p < 0.0001; Netherlands- p = 0.0001; France- p = 0.0033) and neurological ailments (France- p = 0.0001; Netherlands- p < 0.0001) are significantly higher than the total hospitalized patients affected by the particular comorbidity. We have noted that deaths due to liver diseases are least associated with COVID-19 among all comorbidities. Intriguingly, immunodeficiency shows mixed outcomes in death proportions compared to the hospital admitted individuals. Besides, the treatment regime involves drugs like losartan, ACE inhibitors, angiotensin-receptor blockers, Remdesivir, Chloroquine, Hydroxychloroquine, etc. may modulate the severity of the comorbidities. These comorbidities can create chaos in the existing healthcare system and may worsen the disease outcome.