An Update on SARS-CoV-2: Damage-response Framework, Potential Therapeutic Avenues and the Impact of Nanotechnology on COVID-19 Therapy

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End User License Agreement
Contents
Foreword
Preface
List of Contributors
COVID -19 Overview
Anitha Sriram1, Pravin Medtiya1, Srushti Mahajan1, Rahul Kumar2, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Jitender Madan1 and Pankaj Kumar Singh1,*
INTRODUCTION
ORIGIN OF SARS-COV-2
RESERVOIR OF SARS-COV-2
GENOME SEQUENCE
MAJOR EVENTS IN THE TIMELINE OF THE COVID-19 OUTBREAK
REPORTED CONFIRMED CASES, DEATH CASES, AND CASE FATALITY RATE (CFR) OF COVID-19
TYPES OF CORONAVIRUSES AND THEIR OUTBREAK IMPACT
Coronavirus
Taxonomy of Coronavirus
CoronaVirus
FACTS OF FATALLY POTENTIAL BETA CORONAVIRUSES
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Virology of SARS-CoV2
Anitha Sriram1, Ravindra Vasave1, Indrani Maji1, Rahul Kumar2, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Neelesh K. Mehra1 and Pankaj Kumar Singh1,*
INTRODUCTION
DETAILED VIROLOGY OF SARS-COV-2
Size and Content
GENOMIC RNA OF SARS-COV-2
NSPs Role in 2019-nCoV
Structural Proteins
Envelope Protein (E)
Membrane Glycoprotein/matrix Glycoprotein (M)
Nucleocapsid Protein (N)
Spike (S) Protein
Two Subunits S1 and S2 of the Spike Protein
DETAILED COMPOSITION OF TWO SUBUNITS OF 'S' PROTEIN AND THEIR FUNCTIONS
S1 Subunit
S2 Subunit
COMPONENTS AND FUNCTIONS OF S1 SUBUNIT
Components of S1 Subunit
BOUNDARY BETWEEN S1 SUBUNIT AND S2 SUBUNIT (S1/S2')
FUNCTIONS OF S1 SUBUNITS
WHY THE HACE-2 RECEPTOR HAS MORE AFFINITY WITH 2019-NCOV IN COMPARISON TO SARS-COV?
STABILIZATION OF VIRUS-BINDING HOTSPOTS ON HACE2 BY 2019-NCOV
ROLE OF THIOL-DISULFIDE INTERCHANGES IN THE INTERPLAY BETWEEN 'S' PROTEIN AND HACE2
COMPONENTS AND FUNCTIONS OF S2 SUBUNIT
Components of S2 Subunit
FP
HR1 and HR2
FUNCTIONS OF S2 SUBUNIT
SIMILARITY PERCENTAGE (IN TERM OF AMINO ACID SEQUENCE) OF 2019-NCOV WITH THE OTHER COVS
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
SARS-COV-2 Ingress - Triggering COVID-19 Infection
Anitha Sriram1, Yojana Bhor1, Srushti Mahajan1, Rahul Kumar2, Saurabh Srivastava1, Dharmendra Kumar Khatri2, Shashi Bala Singh2 and Pankaj Kumar Singh1,*
INTRODUCTION
ENTRYWAYS OF 2019-NCOV INTO THE HOST CELL
Priming of TMPRSS2 Associated Cleavage for the Fusion of Virus
Endocytosis
Furin Mediated Viral Entry
ROLE OF HOST CELL PROTEOLYTIC CLEAVAGE ON ‘S’ PROTEIN OF SARS-COV-2
TMPRSS2 Role for the Fusion of SARS-COV2
Furin Mediated Proteolytic Cleavage at S1/S2 Frontier
Other Proteases Involved in the Functioning of Activated Spike Protein
WHY VIRAL IMMUNE EVASION IS SEEN IN COVID-19?
Pre-fusion and Post-fusion Conformational States of 2019-nCoV Spike Protein
Role of SPs, NSPs, and Orfs of 2019-nCoV in Host Immune Evasion (Host IFN Response)
Role of Viral VSR (Viral Suppressors of RNA) in Host Immune Evasion
HOW ‘S' PROTEIN OF 2019-NCOV IS ACCOUNTABLE FOR VIRUS WIDESPREAD?
MUTATIONS OF SARS-COV-2 AND EMERGENCE OF SARS-COV-2 VARIANTS
SARS-CoV-2 Variants
Alpha Variant
Beta Variant
Gamma Variant
Delta and Kappa Variants
A New Variant of SARSCOV2 Called “Omicron” Emerging
Genomic Variant Analysis Study
Danger Magnitude Levels of Emerging 2019-nCoV Variants
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Epidemiology of COVID-19
Anitha Sriram1, Yojana Bhor1, Srushti Mahajan1, Rahul Kumar2, Saurabh Srivastava1, Dharmendra Kumar Khatri2, Shashi Bala Singh2 and Pankaj Kumar Singh1,*
INTRODUCTION
LIFE CYCLE OF 2019-NCOV
Adsorption
Penetration Step Or Fusion Step
Uncoating Step
Replication
Transcription
INCUBATION TIME
HOW SARS-COV2 SPREADS?
Person to Person
Airborne Transmission
Fecal Contamination
Fomite Transmission (Contaminated Objects and Surfaces)
Mass Gatherings
Mother to the Baby in Pregnancy Condition
CLINICAL MANIFESTATIONS OF COVID-19 DISEASE
Clinical Symptoms of Mild COVID-19 Disease
Symptoms During the Severity of Disease
Complications of Very Critically Ill COVID-19 Patients
Asymptomatic COVID-19
HIGH RISK OF COVID-19 INFECTION
COVID-19 IN CHILDREN
CASE FATALITY RATE (CFR IN %) OF COVID-19
Recovery Rate
DIAGNOSIS
Radiology Findings
Laboratory Findings in COVID-19
Serological Findings
Immunopathological Findings
Mild COVID-19 Infection
Severe COVID-19 Infection
Hematological Changes
Immunological Marker to Assess Severity
Autopsy Pathological Findings
Pulmonary Findings
Blood
COVID-19 PREVENTION
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Etiology of COVID-19
Anitha Sriram1, Balram Prajapati1, Srushti Mahajan1, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Saurabh Srivastava1 and Pankaj Kumar Singh1,*
INTRODUCTION
STAGES OF COVID-19
Healthy Individual
STAGES OF COVID-19 INFECTION IN DETAIL
Mild COVID-19 Infection: First Stage of Infection
Clinical Signs
Level of Care
Moderate Type of COVID-19 Infection: Second Stage of Infection
Host’s Innate Immune System Consequences Lead To The Progression of COVID-19
Host’s Adaptive Immune System Consequences Leading To Progression of COVID-19
Cytotoxic Action of 2019-nCoV on Host Immune Cells
Clinical Signs
Level of Care
Severe Type of COVID-19 Infection: Third Stage of Infection
Exuberant Cytokine Storm
Enhanced Vascular hyper-Permeability
Diffuse Alveolar Damage (DAD)
Severe Pneumonia
ARDS
Acute Lung Injury (ALI)
Cause for ALI
Complement Activation
Disseminated Intravascular Coagulation (DIC)
Clinical Signs
Level of Care
Critically Ill COVID-19 Infection: Fourth Stage of Infection
Hyper-inflammation Additionally Causes SIRS
SIRS Lead to Septic Shock
Multiple Organ Failure (MOF)
Acute COVID-19 Cardiovascular Syndrome (ACovCS)
Liver Damage
Renal Damage
Ocular Damage
GIT Damage
Olfactory Nerve (Brain) Damage
ADE (Antibody-Dependent Enhancement)
CLINICAL SIGNS
LEVEL OF CARE
BIOMARKERS IN TESTING COVID-19 SEVERITY
Hematological Biomarkers
Biochemical Markers
Coagulation Biomarkers
Inflammatory Biomarkers
Potential New Biomarkers
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Damage Response Framework of COVID-19
Anitha Sriram1, Pravin Medtiya1, Srushti Mahajan1, Indrani Maji1, Rahul Kumar2 and Pankaj Kumar Singh1,*
INTRODUCTION
PATHOGENIC EVENTS
DIRECT CYTOTOXIC EFFECT OF 2019-NCOV ON HOST TARGET CELL
The Fate of 2019-nCoV and its Interaction with the Host
Viral Infection Triggering
DOWNREGULATION OF HACE2 AND DYSREGULATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) IN HOST BODY
When 2019-nCoV Decreases the hACE2 Expression in Lungs and Airways
B0AT1
When 2019-nCoV Drops off the hACE2 Expression in the Intestine
ENDOTHELIAL CELL DAMAGE AND THROMBOINFLAMMATION
DYSREGULATION OF THE IMMUNE RESPONSE
CSS
Consequences of CSS in COVID-19 Patients
ALI
ARDS
DIC
Septic Shock and MOF
PROPOSED FACTS BEHIND THE CAUSE OF CSS
Reduced hACE2
Maladaptive Host Inflammatory Response
Lymphocytopenia
Macrophage Activation Syndrome (MAS)
Toll-like Receptors (TLRs)
Viral Components
Inhibition of IFN Signaling by 2019-nCoV
High Neutrophil to Lymphocyte Ratios (NLR)
Elevated Levels of Extremely pro-inflammatory Th17 Cells That Trigger CSS
Role of Interleukins like IL-6 and IL-17 Causing CSS in COVID-19 Patients
IL-6 Role
IL-17 Role
INFLAMMATORY OR IMMUNOLOGICAL MECHANISMS ASSOCIATED WITH COVID-19 DISEASE
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Drug Repurposing Studies in the Progress to Combat COVID-19
Anitha Sriram1, Pravin Medtiya1, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Jitender Madan1 and Pankaj Kumar Singh1,*
INTRODUCTION
DRUG REPURPOSING
SELECTION OF DRUG CANDIDATES FOR DRUG REPURPOSING TO COMBAT COVID-19 PANDEMIC
WHO (WORLD HEALTH ORGANIZATION) SOLIDARITY TRIAL
Remap-CAP
Recovery
CURRENT THERAPIES USED IN THE TREATMENT OF COVID-19
PREVENTION OF ATTACHMENT OF VIRUS TO THE TARGET CELL HACE2
Soluble hACE2
Soluble Recombinant Human ACE2 Protein (hrsACE2)
Nicotianamine and Glycyrrhizin
Dutasteride
PREVENTION OF VIRUS FUSION WITH HOST CELL
Umifenovir (Arbidol™)
Cathepsin L/B Inhibitor
Trypsin Inhibitors
TMPRSS2 Protease Inhibitors
Camostat Mesylate
Nafamostat Mesylate
Glecaprevir and Maraviroc
PHYTOCHEMICALS THAT MIGHT FIND ACTIVE AGAINST 2019-NCOV
Terpenes and Lignans
Bromhexine
PREVENTION OF VIRAL GENOME REPLICATION
RNA Synthesis Inhibitors
Ribavirin
Remdesivir (RDV)
Favipiravir
Protease Inhibitors
Lopinavir/ritonavir
Darunavir
Danoprevir
Oseltamivir
ANTI-MALARIAL THERAPY
Chloroquine/Hydroxy Chloroquine (HCQ)/Chloroquine Phosphate (CQP)
ANTI-INFLAMMATORY THERAPY
Cytokine Storm Syndrome (CSS) Reducing Drugs and Approaches
Azithromycin
JAK (Janus and kinases) Inhibitors: Both IL-6 and IL-7 Inhibitors
IL-6 Pathway Inhibitors
Tocilizumab
Beta gp130 Fused to the Fc-portion of a Human IgG1 Antibody (sgp130Fc) Protein
Ruxolitinib and Baricitnib
Sarilumab
SERMs (Selective Estrogen Receptor Modulators)
Interleukin-17 (IL-17) Inhibitors
IL-1 Antagonist
IFN-γ Antagonist
TNF-α Antagonists
Extracorporeal Cytokine Removal Therapy (ECRT)
Cytosorb Therapy
CELL AND BIOLOGICAL THERAPY
Mesenchymal Stem Cells (MSCs) Therapy
NK Cells Therapy
CORTICOSTEROID THERAPY
STATINS THERAPY
MULTIPLE DRUG THERAPY
ANTICOAGULANTS
OTHER DRUGS OR AGENTS THAT MAY BE FOUND TO BE USEFUL FOR THE TREATMENT OF COVID-19 INFECTION
Sirolimus
Colchicine
Ivermectin
CRISPR/Cas13d System
RLF-100 or Aviptadil
TRPV4 Inhibitor
Prednisone and HCQ
Nanobodies
Herbal Agents
Nutritional Supplement
Niclosamide
Nitric Oxide (NO) and Epoprostenol
Chlorpromazine (CPZ)
Drugs that Suppress TMPRSS2 Gene Expression
Ebselen
Polypeptide
First Nanobody (Nb11-59) via Inhalational Delivery
USFDA APPROVED COVID-19 DRUGS
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
BIBLIOGRAPHY
Immunotherapeutic Approaches to Combat COVID-19
Anitha Sriram1, Ekta Pardhi1, Indrani Maji1, Rahul Kumar2, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Saurabh Srivastava1 and Pankaj Kumar Singh1,*
INTRODUCTION
NATURAL IMMUNOMODULATORY APPROACH (IMA)
SELECTION OF AN IMMUNOMODULATOR
Beta-glucan
Therapeutic Applications of 1,3 beta-Glucan and its Role in the Therapy of COVID-19
Macrophage Activation Boosts Innate Immunity
Interferon-γ Stimulator
Attenuation of CSS
Pulmonary Cytoprotection
Role of anti-Inflammatory Activity
Enhancing IgA
Approval of Beta-glucan
Dosage Strength of Beta-glucan
Chitosan
Role of Chitosan as an Anti-Inflammatory Activity
The Innate and Adaptive Immune Potentiator Of Chitosan
The Expected Outcome from IMA
Other Immunomodulators that Might find Potential to Treat COVID-19
Fingolimod
Vitamin C (Vit-C)
Vitamin D and E
Vitamin A (Vit-A)
Zinc Supplementation
Immunomodulatory Effect Exhibited by Few Drugs
IFN THERAPY (ENHANCERS OF ANTIVIRAL IMMUNITY)
INTRAVENOUS IMMUNOGLOBULIN (IVIG)
CONVALESCENT PLASMA THERAPY (CP)
MONOCLONAL ANTIBODIES (MAB) THERAPY
Anti-GM-CSF Therapy
CR3022
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Nanotechnology Impact and It’s Future Perspectives on COVID-19 Therapy
Anitha Sriram1, Rahul Kumar, Indrani Maji1, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Saurabh Srivastava1 and Pankaj Kumar Singh1,*
INTRODUCTION
Nanoparticles (NPs)
ADVANTAGES OF NANOPARTICLES IN THE COVID-19 DISEASE
POLYMERIC NPS
MACROPHAGE TARGETING LIGAND COATED PLGA NPS
ACTIVE TARGETING MECHANISM OF LIGAND COATED PLGA NANOPARTICLES MIGHT FIND HIGH POTENTIAL TO COMBAT COVID-19 INFECTION
IMPACT OF ANTI-VIRAL METALLIC NPS APPROACH
NANO VIRICIDES
ROLE OF NANOTECHNOLOGY IN EMERGING CORONAVIRUSES INFECTIONS
NANOTECHNOLOGY EMERGES AS A BUDDING TOOL IN DIAGNOSING COVID-19 DISEASE
Nanohybrids Emerging as Diagnostic Tools in Coronavirus Infections
Nanoparticles Emerging as Diagnostic Tools in Coronavirus Infections
Lateral Flow Assays of 2019nCoV
Field-effect Transistor Nano Biosensor
NANO-BASED GENE THERAPY
Small Interfering RNAs
First Nanobody (Nb11-59) via Inhalational Delivery
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
COVID-19 Vaccines and Vaccination
Anitha Sriram1, Mayur Aalhate1, Rahul Kumar2, Dharmendra Kumar Khatri2, Shashi Bala Singh2, Neelesh K. Mehra1 and Pankaj Kumar Singh1
INTRODUCTION
VACCINE OPTIONS
Antibody Preparation
VACCINE STRATEGIES
VACCINE DESIGNING APPROACHES
Whole Microbe Approach
Inactivated Vaccines
Examples
Live Attenuated Vaccines
Examples
Viral Vector-based Vaccines
Non-Replicating Viral Vector Vaccines
Examples
Replicating Viral Vector Vaccines
Subunit Approach
Examples
Recombinant Protein-based Approaches
Example
Newer Nanotechnology Approach: Virus-like Particles (VLPs) Vaccine
Genetic Approach
RNA-based-vaccines
DNA-based Vaccines
Examples
OTHER TYPES OF VACCINES
Might be Next Generation COVID-19 Vaccine Platform-Artificial Antigen-presenting Cells (aAPCs) Vaccines
COVID-19a/APC (NCT04299724)
WHAT IS THE TARGET ANTIGEN IN COVID-19 VACCINES?
THE EUA AUTHORIZED VACCINES
The 9 COVID-19 Vaccines Approved by the USFDA for EUA (as of November 2021)
The 8 COVID-19 Vaccines approved by the WHO for authorized use or EUA (as of November 2021)
COVID-19 VACCINES ROLL OUT TO COMBAT COVID PANDEMIC SITUATION
Covaxin
Cadila's ZyCoV-D Vaccine
Oxford-AstraZeneca
OTHER VACCINES THAT ARE ROLLING OUT GLOBALLY
Pfizer/BioNTech
Sputnik-V
Moderna (The mRNA-1273) Vaccine
Janssen Vaccine
CoronaVac
Sinopharm
Novavax
Repurposed Vaccines under Clinical Trials
SIDE EFFECTS OF VACCINES
Common Side Effects
At the Injection Site of the Human Body
Rest of the Human Body
FDA Warnings for Both Covishield and Another Oxford AstraZeneca Vaccine
FDA Warnings for both Pfizer-BioNTech and Moderna
FDA Warnings for Johnson & Johnson’s Vaccine
EXPANSION OF BASKET OF COVID-19 VACCINES TO MEET THE GLOBAL SUPPLY- INDISPENSABLE ROLE OF INDIA
COMPARISON OF TOPMOST FIVE VACCINES APPROVED BY WHO UNDER EUA
A RECENT STUDY PROVES THAT SPUTNIK-V IS THE BEST COVID-19 VACCINE
COVID-19 VACCINE IN CHILDREN
The Pfizer-BioNTech COVID-19 Vaccine
VACCINES EFFICACY AGAINST THE VARIANTS OF CONCERN (VOC) THAT ARE EMERGING DURING THE COVID-19 PANDEMIC
Vaccination with Any of the Covid-19 Vaccine as of 21 November 2021
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Turning Towards Phytopharmaceuticals to Revitalize the Immune System to Fight Against COVID-19
Dharmendra Kumar Khatri1, K Pushpa Tryphena1, Rahul Kumar1, Anitha Sriram2, Pankaj Kumar Singh2, Rupinder Kaur Sodhi3, Jitender Madan1 and Shashi Bala Singh1,*
INTRODUCTION
SIGNALING NETWORK AND CASCADE OF IMMUNE ARRANGEMENT
Immune Response Against Virus Infection
Generation of Innate (Non-specific) Immune Response
Role of B-cells Mediated Immunity Against SARS-CoV-2
Role of T Cells in an Immune Response against SARS-CoV-2
MOLECULAR TARGET IN SARS-COV-2 FOR IMMUNE RESPONSE
CELLULAR ADENOSINE TRIPHOSPHATE: OBLIGATORY FOR INNATE IMMUNITY BOOSTING
ATP Promotes the Production of IFN
ATP Facilitates IFN Signaling
ATP Prevents the Cytokine Storm
ATP Thwarts T-cell Apoptosis
PHYTOPHARMACEUTICALS AS IMMUNOMODULATORS
Withania Somnifera
Tinospora Cordifolia
Curcuma Longa
Glycyrrhiza Glabra
Andrographis Paniculata
CHALLENGES, OPPORTUNITIES, AND FUTURE PROSPECTS
CONCLUSION
CLINICAL SIGNIFICANCE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Subject Index
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