Publications by authors named "Mohammad Amjad Kamal"

213 Publications

Structure-Based Identification of Natural Products as SARS-CoV-2 M Antagonist from Using Computational Approaches.

Viruses 2021 Feb 15;13(2). Epub 2021 Feb 15.

Centre for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India.

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (M) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from , commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 M. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 M catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 M with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 M antagonist with higher affinity and drug-likeness.
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http://dx.doi.org/10.3390/v13020305DOI Listing
February 2021

Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges.

Int J Mol Sci 2021 Feb 24;22(5). Epub 2021 Feb 24.

Faculty of Medicine, Al-Azhar University, Damietta 34511, Egypt.

Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor's aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations.
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http://dx.doi.org/10.3390/ijms22052258DOI Listing
February 2021

Sleep Disorders Research From 1945 to 2020: A Bibliometric Analysis.

CNS Neurol Disord Drug Targets 2021 Feb 17. Epub 2021 Feb 17.

Departamento de Bioquímica e BiologiaMolecular, Programa de Pós-Graduação em Bioquímica Toxicológica, UniversidadeFederal de Santa Maria, Santa Maria, RS 97105-900. Brazil.

Background: The objective of the present review is to perform the 1st bibliometric analysis of sleep disorders research.

Methods: The data was retrieved from Scopus in July, 2020 for detail analysis.

Results: The 1st precise document about the sleep disorder was published in 1945. Till 15th July 2020, total 69657 documents were found in Scopus database. Approximately eighty two percent (57013/81.87%) documents are published in the last twenty years (from 2001-2020). We calculated the per year growth rate (GR) of publications (from 2000-onwards). The highest number of documents are published in 2019 (4337/7.90% of 57013) followed by 2018 (4249/7.74% of 57013) and 2017 (3974/7.24% of 57013). Infact the productivity index (PI) for 1950-1960 and 2011-2020 era was found to be 100.21. We also provided the details of the top 50 countries with maximum number of publications (from 1945 to July 2020). The top three (3) countries are USA with 24262 publications (34.83%), followed by UK (5566/8.0%) and Germany (4791/6.87%). We also performed the co-words analysis. Infact total 956643 (0.95 million) keywords were retrieved from 69657 published documents. After critical analysis we categorized them in different groups to show the trend in various domains. In the next phase of the study, only those documents were analyzed which contained the phrase "sleep disorder" in the titles of the publications. Total 3626 documents were found. We calculated the per year growth rate (GR). The continental distribution, the list of top twenty authors, sources/journals, departments or institutes, countries and research documents with highest citations are provided. By VOSviewer analysis, 6752, 36511 and 11473 terms in titles of the manuscripts, abstracts and keywords were recorded, respectively. This may help in describing the overall trend in these publications.

Conclusions: The present study provides a detail list of top authors, departments, countries, sources and top 20 most cited documents. The co-words analysis may help in describing the trends in the field of sleep disorders.
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http://dx.doi.org/10.2174/1871527320666210218085341DOI Listing
February 2021

Cellular and molecular mechanisms of Dementia: Decoding the causal link of Diabetes Mellitus in Alzheimer's disease.

CNS Neurol Disord Drug Targets 2021 Feb 11. Epub 2021 Feb 11.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah. Saudi Arabia.

Dementia and diabetes are the two major disorders that are linked at both biochemical and molecular levels which is due to the existing similarities between pancreatic beta-cells and neuronal cells at the transcription and translational levels. Both diseases have similar causative genes or factors and dementia is one of the advanced complications in about 50-52% of patients with type 2 diabetes mellitus (T2DM). Further, patients with T2DM are at a higher risk of neuronal degeneration and Alzheimer's disease (AD). Dementia, which is most common in AD, is associated with diminished insulin receptors by nearly 80%. The impairment in insulin signaling thus leads to the development of dementia and AD. Biochemical changes in 'tau' protein and amyloid-beta proteins, make them critical players in the formation of plaques in patients with dementia and AD. Here, we decode various cellular and molecular mechanisms associated with the development of dementia in patients with diabetes and AD.
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http://dx.doi.org/10.2174/1871527320666210212114116DOI Listing
February 2021

Special issue: Cancer nanotherapeutics: Targeted medicine, therapeutic vaccination and challenges with cancer nanomedicines.

Semin Cancer Biol 2021 Feb 8;69:1-4. Epub 2021 Feb 8.

West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.semcancer.2021.02.003DOI Listing
February 2021

The computational intervention of macrolide antibiotics in the treatment of COVID-19.

Curr Pharm Des 2021 Jan 25. Epub 2021 Jan 25.

West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan. China.

The spike (S) glycoprotein of SARS coronavirus (SARS-CoV-2) and human Angiotensin-converting enzyme 2 (ACE2), are both considered the key factors for the initiation of virus infection. The present work is an effort for a computational target to block the spike proteins (S) and ACE2 receptor proteins with Macrolide antibiotics like Azithromycin, (AZM), Clarithromycin (CLAM) and Erythromycin (ERY) along with RNA-dependent RNA polymerase (RdRp). These compounds were able to block the residues (Arg553, Arg555, and Ala558) surrounding the deep grove catalytic site (Val557) of RdRp and thus plays an important role in tight blocking of enzyme active site. Reference drug Remdesivir was used to compare the docking score of antibiotics with RdRp. Docking value exhibited good binding energy (-7.7 up to -8.2 kcal/mol) with RdRp, indicating their potential as a potent RdRp inhibitor. Interaction of CLAM and ERY presented low binding energy (-6.8 and -6.6) with the ACE2 receptor. At the same time, CLAM exhibited a good binding affinity of -6.4 kcal/mol, making it an excellent tool to block the attachment of spike protein to ACE2 receptors. Macrolides not only affected the attachment to ACE2 but also blocked the spike proteins further, consequently inhibiting the internalization in the host cell. Three Alkyl bonds between Arg555, Ala558, and Met542 by CLAM and two Alkyl bonds of Arg624 and Lys621 by ERY plays an important role for RdRp inactivation that can prevent the rise of newly budded progeny virus. These macrolides interacted with the main protease protein in the pocket responsible for the dimerization and catalytic function of this protein. The interaction occurred with residue Glu166, along with the catalytic residues (Tyr343, and His235) of Endoribonuclease (NSP15) protein. The present study gives three-way options either by blocking S proteins or ACE2 receptor proteins or inhibiting RdRp to counter any effect of COVID-19 by macrolide and could be useful in the treatment of COVID-19 till some better option available.
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http://dx.doi.org/10.2174/1381612827666210125121954DOI Listing
January 2021

Emerging therapeutic approaches to COVID-19.

Curr Pharm Des 2021 Jan 25. Epub 2021 Jan 25.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025. India.

Coronavirus diseases (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), which is a positive single-stranded RNA virus having a large genome ~30 kb. SARS-CoV-2 is zoonotic and highly contagious, causing severe pneumonia-like symptoms. The efficacy of the different potential drug and drug candidates against COVID-19 has been investigated which are under various stages of clinical trials. The drugs effective against SARS, and Middle east respiratory syndrome (MERS), have been proposed to have a high potential for the treatment of COVID-19. Here, we selected plant-based materials implicated in the prevention and therapy of COVID-19. The vaccine has shown impressive results in producing antibodies against SARS-CoV2 and has been evaluated for safety, tolerance, and preliminary immunogenicity. Similarly, DNA/RNA-based therapy shown high clinical significance. The plant produces secondary metabolites in response to viral infection to protect them. Many nanomaterials produced by carbohydrates and lipids been exploited for their in-vitro and in-vivo delivery of antiviral therapeutics. Different classes of secondary metabolites have a different mechanism to counter virus attacks. While some natural medicines in the form of vitamins, minerals, herbs, and other nutrients help to enhance immunity, such measures should not replace social distancing, quarantining special care to protect from COVID-19. The standards of reporting were in accordance with the PRISMA guidelines.
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http://dx.doi.org/10.2174/1381612827666210125160703DOI Listing
January 2021

Molecular docking of alpha-enolase to elucidate the promising candidates against Streptococcus pneumoniae infection.

Daru 2021 Feb 3. Epub 2021 Feb 3.

Kulliyyah of Allied Health Sciences, International Islamic University Malaysia (IIUM), 25200, Kuantan, Pahang, Malaysia.

Purpose: To predict potential inhibitors of alpha-enolase to reduce plasminogen binding of Streptococcus pneumoniae (S. pneumoniae) that may lead as an orally active drug. S. pneumoniae remains dominant in causing invasive diseases. Fibrinolytic pathway is a critical factor of S. pneumoniae to invade and progression of disease in the host body. Besides the low mass on the cell surface, alpha-enolase possesses significant plasminogen binding among all exposed proteins.

Methods: In-silico based drug designing approach was implemented for evaluating potential inhibitors against alpha-enolase based on their binding affinities, energy score and pharmacokinetics. Lipinski's rule of five (LRo5) and Egan's (Brain Or IntestinaL EstimateD) BOILED-Egg methods were executed to predict the best ligand for biological systems.

Results: Molecular docking analysis revealed, Sodium (1,5-dihydroxy-2-oxopyrrolidin-3-yl)-hydroxy-dioxidophosphanium (SF-2312) as a promising inhibitor that fabricates finest attractive charges and conventional hydrogen bonds with S. pneumoniae alpha-enolase. Moreover, the pharmacokinetics of SF-2312 predict it as a therapeutic inhibitor for clinical trials. Like SF-2312, phosphono-acetohydroxamate (PhAH) also constructed adequate interactions at the active site of alpha-enolase, but it predicted less favourable than SF-2312 based on binding affinity.

Conclusion: Briefly, SF-2312 and PhAH ligands could inhibit the role of alpha-enolase to restrain plasminogen binding, invasion and progression of S. pneumoniae. As per our investigation and analysis, SF-2312 is the most potent naturally existing inhibitor of S. pneumoniae alpha-enolase in current time.
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http://dx.doi.org/10.1007/s40199-020-00384-3DOI Listing
February 2021

Functional Neuroproteomics: An imperative approach for unravelling protein implicated complexities of brain.

CNS Neurol Disord Drug Targets 2021 Feb 2. Epub 2021 Feb 2.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

A proteome is defined as a comprehensive protein set either of an organ or an organism at a given time and under specific physiological conditions and accordingly, the study of nervous system's proteomes is called Neuroproteomics. In the neuroproteomics process, various pieces of the nervous system are "fragmented" to understand the dynamics of each given sub-proteome in a much better way. Functional proteomics addresses the organisation of proteins into complexes, and formation of organelles from these multiprotein complexes that control various physiological processes. Current functional studies of neuroproteomics mainly talk about the synapse structure and its organisation, the major building site of the neuronal communication channel. The proteomes of synaptic vesicle, presynaptic terminal, and postsynaptic density, have been examined by various proteomics techniques. The objective of functional neuroproteomics is to solve the proteome of single neurons or astrocytes grown in cell cultures or from the primary brain cells isolated from tissues under various conditions; to identify set of proteins which characterize a specific pathogenesis; or to determine the group of proteins making up post-synaptic or pre-synaptic densities. It is very usual to try to solve a particular sub-proteome like the heatshock response proteome, or the proteome responding to inflammation. Posttranslational protein modifications alter their functions and interactions. The techniques to detect synapse phosphoproteome are available however, those for the analysis of ubiquitination and sumoylation, are under development.
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http://dx.doi.org/10.2174/1871527320666210202121624DOI Listing
February 2021

A cross-talk between gut microbiome, salt and hypertension.

Biomed Pharmacother 2021 Feb 2;134:111156. Epub 2021 Jan 2.

Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Cardiac disorders contribute to one of the major causes of fatality across the world. Hypertensive patients, even well maintained on drugs, possess a high risk to cardiovascular diseases. It is, therefore, highly important to identify different factors and pathways that lead to risk and progression of cardiovascular disorders. Several animals and human studies suggest that taxonomical alterations in the gut are involved in the cardiovascular physiology. In this article, with the help of various experimental evidences, we suggest that the host gut-microbiota plays an important in this pathway. Short chain fatty acids (SCFAs) and Trimethyl Amine -n-Oxide (TMAO) are the two major products of gut microbiome. SCFAs present a crucial role in regulating the blood pressure, while TMAO is involved in pathogenesis of atherosclerosis and other coronary artery diseases, including hypertension. We prove that there exists a triangular bridge connecting the gap between dietary salt, hypertension and gut microbiome. We also present some of the dietary interventions which can regulate and control microbiota that can prevent cardiovascular complications.We strongly believe that this article would improve the understanding the role of gut microbiota in hypertension, and will be helpful in the development of novel therapeutic strategies for prevention of hypertension through restoring gut microbiome homeostasis in the near future.
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http://dx.doi.org/10.1016/j.biopha.2020.111156DOI Listing
February 2021

Exosomes: Critical mediators of tumour microenvironment reprogramming.

Curr Med Chem 2020 Dec 16. Epub 2020 Dec 16.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

Tumour microenvironment (TME) is a resident of a variety of cells, which devoted to the heterogeneous population of the tumour. TME establishes a communication network for crosstalk and signalling between tumour cells, stroma, and other interstitial cells. The cross-communication drives the reprogramming of TME cells, which promote cancer progression and metastasis via diverse signalling pathways. Recently, TME-derived exosomes are recognized as critical communicators of TME cell reprogramming. This review addresses the role of TME-derived exosomes in the modulation of stroma, including reprogramming the stromal cells, ECM and tumour cell metabolism, as well as neoplastic transformation. Subsequently, we described the role of exosomes in pre-metastatic niche development, maintenance of stemness and tumour vasculature as well as development of drug resistance. We also explored tumour-derived exosomes in precision, including diagnosis, drug delivery, and vaccine development. We discussed the currently established bioengineered exosomes as carriers for chemotherapeutic drugs, RNAi molecules, and natural compounds. Finally, we presented tetraspanin and DNAbased precision methods for the quantification of tumour-derived exosomes. Overall, TME-derived exosome-mediated reprogramming of TME and precision strategies could illuminate the potential mechanisms for targeted therapeutic intervention.
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http://dx.doi.org/10.2174/0929867328666201217105529DOI Listing
December 2020

Prevalence of Headache in Patients With Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis of 14,275 Patients.

Front Neurol 2020 27;11:562634. Epub 2020 Nov 27.

Department of Neurology, Headache Centre, San Lazzaro Hospital, Alba, Italy.

Coronavirus disease 2019 (COVID-19) started to spread globally since December 2019 from Wuhan, China. Headache has been observed as one of the clinical manifestations in COVID-19 patients. We aimed to conduct a comprehensive systematic review and meta-analysis to estimate the overall pooled prevalence of headache in COVID-19 patients. PubMed, Scopus, ScienceDirect, and Google Scholar databases were searched to identify studies published between December 2019 and March 2020. Adult (≥18 years) COVID-19 patients were considered eligible. We used random-effects model to estimate the pooled prevalence with 95% confidence intervals (CIs). Quality assessment was done using the Joanna Briggs Institute critical appraisal tools. This study is registered with PROSPERO (CRD42020182529). We identified 2,055 studies, of which 86 studies ( = 14,275, 49.4% female) were included in the meta-analysis. Overall, the pooled prevalence of headache in COVID-19 patients was 10.1% [95% CI: 8.76-11.49]. There was no significant difference of headache prevalence in severe or critical vs. non-severe (RR: 1.05, = 0.78), survived (recovered or discharged) vs. non-survived (RR: 1.36, = 0.23), and ICU vs. non-ICU (RR: 1.06, = 0.87) COVID-19 patients. We detected 64.0, 34.9, and 1.1% of the included studies as high, moderate, and low quality, respectively. From the first 4-month data of the outbreak, headache was detected in 10.1% of the adult COVID-19 patients.
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http://dx.doi.org/10.3389/fneur.2020.562634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728918PMC
November 2020

Viral Diseases and Natural Products: Prospects in COVID-19 Treatment (Part-I).

Curr Pharm Des 2020 ;26(41):5221-5223

Southwest Medical University, China.

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http://dx.doi.org/10.2174/138161282641201126124050DOI Listing
December 2020

Particulate β-glucan activates early and delayed phagosomal maturation and autophagy within macrophage in a NOX-2 dependent manner.

Life Sci 2021 Feb 10;266:118851. Epub 2020 Dec 10.

Immunobiochemistry Laboratory, Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India. Electronic address:

Aims: Macrophage is known to readily engulf any particulate material they encounter, including invading microbes and nano- or micro-particles. While recent studies show that some microparticles (MP) are immunogenic even without drug-cargo, the mechanism underlying this phenomenon is yet unclear. Phagocytosis induces NADPH oxidase-2 (NOX-2) mediated ROS generation that is reported to regulate antibacterial autophagy. We therefore, investigated the role of NOX-2 derived ROS in phagosomal maturation and autophagy induction in response to phagocytic uptake of two kinds of polymeric biodegradable and biocompatible microparticles: yeast-derived β-glucan particles (YDGP) and poly-(D, L-Lactic Acid) microparticles (PMP).

Main Methods: J774A.1 macrophage wereas exposed to polymeric particles and the immune responses: ROS, phagosomal maturation and autophagy induction, were examined by assays including NBT, DCFH-DA, NADPH-Oxidase activity, Lysotracker and Acridine Orange. Further, the LC3 and NOX-2 expression were validated by RT-PCR, immunofluorescence assay and Western blotting. Antimicrobial activity of both MP was examined by CFU counting after administration to Mycobacterium tuberculosis and Salmonella typhimurium infected macrophage.

Key Findings: YDGP induces phagosomal maturation and acidic vesicle accumulation at 30 min and 24 h post-exposure, much more proficiently than that by PMP. YDGP exposure also induced NOX-2 dependent expression of light chain 3 (LC3-II), further confirmed as autophagy activation via autophagic flux assay with autophagolysosome inhibitor bafilomycin A1. Additionally, YDGP displayed superior anti-microbial activity than that by PMP.

Significance: The induction of NOX-2-dependent autophagy and antimicrobial activity exhibited by particulate glucans has significant implications in harnessing these drug delivery vehicles as potential 'value-added' autophagy-mediated therapeutics in future.
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http://dx.doi.org/10.1016/j.lfs.2020.118851DOI Listing
February 2021

Natural Products Homoharringtonine and Emetine Alkaloids for SARSCoV-2 Treatment Options.

Curr Pharm Des 2020 Dec 10. Epub 2020 Dec 10.

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

Background: Viruses are known as the major causative agents for infectious diseases globally. The coronaviruses are one of the serious pathogens to cause serious diseases in humans. Recently identified SARS-CoV-2 from Wuhan City, China has emerged as a serious threat to human health and caused a global pandemic. Bats have been confirmed as a primary source of infection. The vaccination of the human population and animals serving as a potential reservoir is a straight forward strategy to control the transmission of any pathogen to humans. Natural products from many herbal plants are well known to have novel antiviral properties and evaluated against various viral diseases. There are many alkaloids have shown to be effective against coronaviruses.

Methods: Recently, the antiviral efficacy of natural alkaloids known as Homoharringtonine (HTT) and Emetine has been evaluated and provided promising results against coronaviruses including SARS-CoVs. These alkaloids may be very useful and can be used as antivirals against SARS-CoV-2 because they have already been reported to inhibit the replication of SASRS-CoV and other viruses in cell lines.

Conclusion: This review specifically focuses on the recent findings of these alkaloids against coronaviruses and possible treatment options for SARS-CoV-2. It is expected that natural products as alkaloids from herbal plants could be considered as novel and valuable candidates for the new antiviral drugs against SARS-CoV-2.
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http://dx.doi.org/10.2174/1381612826666201210121858DOI Listing
December 2020

Inhibits Growth and Migration of Lung Cancer Cells through Regulating p53-Bcl2 and MMPs Pathways.

Am J Chin Med 2020 9;48(8):1941-1953. Epub 2020 Dec 9.

School of Life Sciences, University of Technology Sydney, NSW 2007, Australia.

has been shown to possess antitumor activity. This study investigated the effects and mechanisms of extract (ACE) on growth and migration of human non-small cell lung cancer A549 cells. The effect of ACE on cell viability was determined by MTT assay and fluorescent live-cell imaging. The apoptotic effect of ACE was determined by cell cycle distribution using flow cytometry. A P53-mediated apoptosis pathway was identified by measuring protein expression of p53 and Bcl-2 with Western blotting. Additionally, mRNA expression of p53 and -2 and was detected by qRT-PCR. The effect of ACE on cancer cell migration was confirmed by a wound-healing assay. Expression of MMP-2 and MMP-9 at the protein and gene levels was determined by western blot and qRT-PCR analysis. This study demonstrates the inhibitory effect of ACE on A549 cell proliferation in a dose-response manner with an [Formula: see text]. It was determined that ACE concentration at [Formula: see text] induced cell cycle arrest at S phase in A549 cells. The apoptosis-regulating protein p53 expression was enhanced and also associated with the downregulation of Bcl-2 in ACE treatment cells. The mRNA expression of and associated with was consistent with protein expression. The inhibition of migration of cancer cells treated with ACE was clearly evident. At the same time, suppression of expression of MMP-2 and MMP-9 at protein and mRNA levels was observed. The findings of this study highlight ACE as a potential agent of adjuvant therapy for lung cancer.
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http://dx.doi.org/10.1142/S0192415X20500974DOI Listing
December 2020

ROS-responsive nanomedicine: Towards targeting the breast tumor microenvironment.

Curr Med Chem 2020 Dec 8. Epub 2020 Dec 8.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

The breast tumor microenvironment (TME) promotes drug resistance through an elaborated interaction of TME components mediated by reactive oxygen species (ROS). Despite a massive accumulation of data concerning the targeting the ROS, but little is known about the ROS-responsive nanomedicine for targeting breast TME. This review submits the ROS landscape in breast TME, including ROS biology, ROS mediated carcinogenesis, reprogramming of stromal and immune cells of TME. We also discussed ROS-based precision strategies for imaging TME, including molecular imaging techniques with advanced probes, multiplexed methods, and multi-omic profiling strategies. ROS-responsive nanomedicine also describes various therapies, such as chemo-dynamic, photodynamic, photothermal, sono-dynamic, immune, and gene therapy for BC. We expound ROS-responsive primary delivery systems for chemotherapeutics, phytochemicals, and immunotherapeutics. This review also presents recent updates on nano-theranostics for simultaneous diagnosis and treatment of BCs. We assume that review on this advancing field will be beneficial to the development of ROS-based nanotheranostics for BC.
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http://dx.doi.org/10.2174/0929867328666201209100659DOI Listing
December 2020

Micro-RNAs in the regulation of immune response against SARS COV-2 and other viral infections.

J Adv Res 2020 Dec 2. Epub 2020 Dec 2.

West China School of Nursing / Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.

Background: Micro-RNAs (miRNAS) are non-coding, small RNAs that have essential roles in different biological processes through silencing genes, they consist of 18-24 nucleotide length RNA molecules. Recently, miRNAs have been viewed as important modulators of viral infections they can function as suppressors of gene expression by targeting cellular or viral RNAs during infection.

Aim Of Review: We describe the biological roles and effects of miRNAs on SARS-CoV-2 life-cycle and pathogenicity, and we discuss the modulation of the immune system with micro-RNAs which would serve as a new foundation for the treatment of SARS-COV2 and other viral infections.

Key Scientific Concepts Of Review: miRNAs are the key players that regulate the expression of the gene in the post-transcriptional phase and have important effects on viral infections, thus are potential targets in the development of novel therapeutics for the treatment of viral infections. Besides, micro-RNAs (miRNAs) modulation of immune-pathogenesis responses to viral infection is one of the most-known indirect effects, which leads to suppressing of the interferon (IFN-α/β) signalling cascade or upregulation of the IFN-α/β production another IFN-stimulated gene (ISGs) that inhibit replication of the virus. These virus-mediated alterations in miRNA levels lead to an environment that might be either enhance or inhibit virus replication.
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http://dx.doi.org/10.1016/j.jare.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708232PMC
December 2020

Drug designing against NSP15 of SARS-COV2 via high throughput computational screening and structural dynamics approach.

Eur J Pharmacol 2021 Feb 1;892:173779. Epub 2020 Dec 1.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW, 2770, Australia; Novel Global Community Educational Foundation, Australia.

The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2. NSP15 is an attractive druggable target due to its critical role in SARS-CoV2 replication and virulence in addition to interference with the host immune system. Here in the present study, we integrated the high throughput computational screening and dynamic simulation approach to identify the most promising candidate lead compound against NSP15.5-fluoro-2-oxo-1H-pyrazine-3-carboxamide (favipiravir), (3R,4R, 5R)-3,4-Bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one) remedesivir, 1,3-thiazol-5-ylmethyl N-[(2S,3S, 5S)-3-hydroxy-5-[[(2 S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (ritonavir), ethyl (3R,4R, 5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate (oseltamivir), and (2 S)-N-[(2S,4S, 5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (lopinavir) were chosen as a training set to generate the pharmacophore model. A dataset of ~140,000 compounds library was screened against the designed pharmacophore model and 10 unique compounds were selected that passed successfully through geometry constraints, Lipinski Rule of 5, and ADME/Tox filters along with a strong binding affinity for NSP15 binding cavity. The best fit compound was selected for dynamic simulation to have detailed structural features critical for binding with the NSP15 protein. Given our detailed integrative computational analysis, a Small molecule (3,3-Dimethyl-N-[4-(1-piperidinylcarbonyl) phenyl] butanamide) with drug-like properties and high binding affinity with the NSP15 is proposed as a most promising potential drug against COVID-19. The current computational integrative approach may complement high-throughput screening and the shortlisted small molecule may contribute to selective targeting of NSP15 to stop the replication of SARS-CoV2.
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http://dx.doi.org/10.1016/j.ejphar.2020.173779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706467PMC
February 2021

Therapeutic management of COVID-19 patients: Clinical manifestation and limitations.

Curr Pharm Des 2020 Nov 24. Epub 2020 Nov 24.

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar New Delhi 110025. India.

Coronavirus disease-2019 (COVID-19) is a respiratory tract infection, accompanied with severe or fatal pneumonia like symptoms and sometime death. It has posed to be an ongoing global health emergency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to a sudden outbreak and a large number of infections and deaths, it became a major concern all over the world. The options available as effective therapeutic, should be urgently exercised to handle this pandemic disease. So far, no specific and accurate anti-SARS-CoV-2 treatment is recommended because of the absence of sufficient clinical evidence. In such cases, the clinical use of available drugs is always considered to be on top priority. A broad-spectrum antiviral agent, Remdesivir is found effective in many cases and recommended by many clinicians in many countries. This drug acts as a potential inhibitor of viral RNA-dependent RNA polymerase protein, and thus likely to be efficacious in SARS-CoV-2 infection. Tocilizumab is currently recommended by many hospitals as an alternative treatment for critically ill COVID-19 patients. The tocilizumab has been administered to control cytokine storms that occurred due to the release of proinflammatory cytokine including interleukin 6. Chloroquine and hydroxychloroquine were also used in hospitals, to handle severe COVID-19 patients. Currently, plasma therapy has been exercised as a therapeutic alternative, especially to handle severe COVID-19 patients. In addition, herbal medicines are expected to play significant role in the control and prevention of COVID-19. All these therapeutic options have their advantages and limitations. This review highlights the therapeutic potential of these available drugs, along with their mechanism of action and shortcomings. We have provided detailed information on available therapeutic options, which have proved to be effectual in improving clinical symptoms of severe COVID-19 patients.
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http://dx.doi.org/10.2174/1381612826666201125112719DOI Listing
November 2020

Coronavirus Disease -2019 (COVID-19) in 2020: A Perspective Study of a Global Pandemic.

Curr Pharm Des 2020 Nov 17. Epub 2020 Nov 17.

School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri. India.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is responsible for the coronavirus disease- 2019 (COVID-19) pandemic, which was first reported from Wuhan, China in late 2019. Its infection spread to thousands of people globally within a short span of time with a progressive trend towards mortality of citizens. Posing a potential public health threat, SARS-CoV-2 progressed from animal-to-human to human-to-human transmission with symptoms ranging from little to no illness to persons severely ill to many deaths, confirming two criteria for declaring COVID-19 a pandemic. The disease shows a progressive trend in symptomology, ranging from mild to severe pneumoniae to respiratory and multi-visceral failure that often shows trend to death of patients with comorbidity within a short span of time. Intensive research efforts on different aspects of this human pathogen are underway across the globe towards elucidating viral transmission routes and the mechanisms employed to overcome host defense responses. With huge infective potential, studies are being carried out vigorously to develop effective diagnostics and therapeutic interventions including re-purposing antivirals and other potential inhibitors. Herein, we describe the taxonomic classification of SARSCoV-2; the structural organization of its genome; its infectivity, transmission, and receptor interaction; and we summarize risk assessment and approaches used in preventing infection. Finally, we discuss important aspects of the development of diagnostic tools and therapeutic countermeasures that have potential to help in controlling the COVID-19 pandemic.
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http://dx.doi.org/10.2174/1381612826666201118112912DOI Listing
November 2020

The impact of traditional plants and their secondary metabolites in the discovery of COVID-19 treatment.

Curr Pharm Des 2020 Nov 17. Epub 2020 Nov 17.

Yunnan Herbal Laboratory, School of Ecology and Environmental Sciences, Yunnan University, Kunming 650091,Yunnan. China.

Background: Coronavirus Disease-2019 belongs to the family of viruses which cause a serious pneumonia along with fever, breathing issues and infection of lungs for the first time in China and later spread worldwide.

Objective: Several studies and clinical trials have been conducted to identify potential drugs and vaccines for Coronavirus Disease-2019. The present study listed natural secondary metabolites identified from plant sources with antiviral properties and could be safer and tolerable treatment for Coronavirus Disease-2019.

Methods: A comprehensive search on the reported studies was conducted using different search engine such as Google scholar, SciFinder, Sciencedirect, Medline PubMed, and Scopus for the collection of research articles based on plantderived secondary metabolites, herbal extracts, and traditional medicine for coronavirus infections.

Results: Status of COVID-19 worldwide and information of important molecular targets involved in COVID-19 is described and through literature search, is highlighted that numerous plant species and their extracts possess antiviral properties and studied with respect to Coronavirus treatments. Chemical information, plant source, test system type with mechanism of action for each secondary metabolite is also mentioned in this review paper.

Conclusion: The present review has listed plants that have presented antiviral potential in the previous coronavirus pandemics and their secondary metabolites which could be significant for the development of novel and a safer drug which could prevent and cure coronavirus infection worldwide.
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http://dx.doi.org/10.2174/1381612826666201118103416DOI Listing
November 2020

Synthesis, anticancer evaluation and molecular docking studies of methotrexate's novel Schiff base derivatives against malignant glioma cell lines.

J Biomol Struct Dyn 2020 Nov 13:1-13. Epub 2020 Nov 13.

Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences and Technology (NUST), Islamabad, Pakistan.

Recent years have witnessed advancement in cancer research that has led to the development of improved cytotoxic therapies with reduced side effects. Methotrexate (MTX) is a commonly used anticancer drug having robust activity, but with serious side effects. Several derivatives of MTX have been reported by modification at different sites to reduce its side effects and enhance efficacy. The current work describes the development of active MTX Schiff base derivatives by treating MTX with several aldehydes viz 2-chlorobenzaldehyde, 3-nitrobenzaldehyde, 5-chloro-2-hydroxybenz-aldehyde, 2-hydroxy-5-nitrobenzaldehyde, 2-thiocarboxyaldehyde, trans-2-pentenal and glutaraldehyde. Newly synthesized derivatives were evaluated for their anticancer potential against human malignant glioma U87 (MG-U87) cell lines at different concentrations of 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μm, 6.25 μm and 0 μM. MTX derivatives with 2-Chlorobenzaldehyde (IC ∼100 μM), 2-Thiocarboxyaldehyde (IC <200 μM) and 2- Pentenal (IC ∼250 μM) showed much better activity at 100 µM compared to 400 µM concentration of MTX. Molecular docking studies were performed that showed a good correlation with the results obtained from experiments. The excellent agreement between molecular modeling and growth inhibition assay shows that the binding mode hypothesis is justly close to the experimentally biological values, therefore, may prove helpful for further lead optimization and clinical trials. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1844053DOI Listing
November 2020

A critical transcription factor NF-κB as a cancer therapeutic target and its inhibitors as cancer treatment options.

Curr Med Chem 2020 Nov 11. Epub 2020 Nov 11.

King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589. Saudi Arabia.

Nuclear Factor-κappa B (NF-κB) is a family of critical transcription factors of inflammatory pathway and plays an imperative role in the progression of various cancers such as breast, lung, liver, pancreatic, prostate and multiple types of lymphoma. NF-κB develops an inherent relationship between inflammation and cancer. It is a crucial factor which controls the ability of malignant and pre-neoplastic cells to prevent programmed cell death-based tumor-surveillance channels. Due to its high significance in the onset and progression of various cancers, it has become an excellent target for cancer therapy. The emerging targeted therapies provide a lot of hope, whereby a single protein or generally the target enzyme is completely blocked. Several natural compounds have shown anticancer and anti-inflammatory activities by inhibiting NF-κB pathway in various cancer types. About 750 natural and synthetic inhibitors of the NF-κB have been reported. These inhibitors include microbial and viral proteins, small RNA/DNA, antioxidants, small molecules, peptides, and engineered constitutively active polypeptides, all of which may inhibit canonical and alternative NF-κB pathways. Thus, blocking or targeting the NFκB-signaling pathways by using natural and synthetic compounds could be a potential mechanism to cure the NF-κB induced tumors.
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http://dx.doi.org/10.2174/0929867327666201111142307DOI Listing
November 2020

E6 and E7 oncoproteins: Potential targets of cervical cancer.

Curr Med Chem 2020 Nov 11. Epub 2020 Nov 11.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.
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http://dx.doi.org/10.2174/0929867327666201111145546DOI Listing
November 2020

mTor Targeting by Different Flavonoids for Cancer Prevention.

Curr Med Chem 2020 Nov 9. Epub 2020 Nov 9.

King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589. Saudi Arabia.

Over the past several decades, plant-derived products (phytochemicals) have been suggested to possess immense therapeutic potential. Among these phytochemicals, different flavonoids have been reported for their potent anticancer activity. To exhibit their anticancer potential, these flavonoids modulate different signaling pathways. Among these pathways, the mammalian target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade has been suggested as a pivotal modulator of cell survival, proliferation, and death/apoptosis. Hence, targeting this cascade could be an ideal strategy to alleviate apoptosis and inhibit proliferation in different forms of cancer. The targeting of PI3K/Akt/mTOR by flavonoids have been well documented in the scientific literature. In the current communication, we have covered the anticancer potential of various flavonoids especially flavones, flavanols, and isoflavones that include apigenin, luteolin, biacalein, tangeretin, epigallocatechin-3-gallate, genistein, and diadzein especially dealing with mTOR targeting.
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http://dx.doi.org/10.2174/0929867327666201109122025DOI Listing
November 2020

SARS-CoV-2 M inhibitors: identification of anti-SARS-CoV-2 M compounds from FDA approved drugs.

J Biomol Struct Dyn 2020 Nov 5:1-16. Epub 2020 Nov 5.

Center for Bioinformatics, Computational and System Biology, Pathfinder Research and Training Foundation, Greater Noida, India.

Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (M), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 M using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >-7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 M were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 M revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using enzyme inhibition and studies against SARS-CoV-2 infection. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1842807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651494PMC
November 2020

Current Challenges in the Management of Neurological Disorders (Part-II).

Curr Pharm Des 2020 ;26(37):4687-4689

Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.

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http://dx.doi.org/10.2174/138161282637200925103303DOI Listing
January 2020

Cardiac Biomarkers in Stroke, Alzheimer's Disease, and Other Dementia. Are They of Use? A Brief Overview of Data from Recent Investigations.

CNS Neurol Disord Drug Targets 2020 Oct 5. Epub 2020 Oct 5.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia.

Conventionally cardiac biomarkers are recognized as an essential tool to investigate the presence or progression of various cardiovascular diseases. However, in recent years data from several clinical trials have successfully sorted out the utility of cardiac biomarkers in diseases that are not primarily regarded as "cardiac diseases," especially neurological diseases. Results of freshly published trials have endorsed the use of cardiac biomarkers in various forms of stroke and dementia, including Alzheimer's disease. Alzheimer's disease is also one of the other CNS conditions where measuring cardiac biomarkers have found to be useful. Cardiac biomarkers can be helpful in two ways. Firstly, to assess the secondary involvement of the heart during the progression of the primary disease. Secondly, they can be useful in the diagnosis and prognosis of the primary condition itself. In this short review, we have collected encouraging results from recent studies that show the importance of the most widely recognized cardiac biomarkers in two of the most prominent neurological diseases of the current world, i.e., stroke and dementia.
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http://dx.doi.org/10.2174/1871527319666201005171003DOI Listing
October 2020

miRNAs in SARS-CoV 2: A Spoke in the Wheel of Pathogenesis.

Curr Pharm Des 2020 Oct 1. Epub 2020 Oct 1.

Department of Applied Physics, Aalto University, Espoo,. Finland.

Introduction: The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an increased mortality rate across the globe. However, the underlying mechanism of SARS-CoV-2 altering human immune response is still elusive. The existing literature on miRNA mediated pathogenesis of RNA virus viz. Dengue virus, West Nile virus, etc. raises a suspicion that miRNA encoded by SARS-CoV-2 might facilitate virus replication and regulate the host's gene expression at the post-transcriptional level.

Methods: We investigated this possibility via computational prediction of putative miRNAs encoded by the SARS-CoV-2 genome using a novel systematic pipeline that predicts putative mature-miRNA and their targeted genes transcripts. To trace down if viral-miRNAs targeted the genes critical to the immune pathway, we assessed whether mature miRNA transcripts exhibit effective hybridization with the 3'UTR region of human gene transcripts. Conversely, we also tried to study human miRNA-mediated viral gene regulation to get insight into the miRNA mediated offense and defense mechanism of viruses and their host organisms in too.

Results: Our analysis led us to shortlist six putative miRNAs that target, majorly, genes related to cell proliferation/differentiation/signaling, and senescence. Nonetheless, they also target immune-related genes that directly/indirectly orchestrate immune pathways like TNF (Tumor Necrosis Factor) signaling and Chemokine signaling pathways putatively serving as the nucleus to cytokine storms.

Conclusion: Besides, these six miRNAs were found to conserved so far across 80 complete genomes of SARS-CoV-2 (NCBI Virus, last assessed 12 April 2020) including Indian strains that are also targeted by 7 human miRNAs and can, therefore, be exploited to develop MicroRNA-Attenuated Vaccines.
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http://dx.doi.org/10.2174/1381612826999201001200529DOI Listing
October 2020