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1.
Cellular Signalling ; : 110559, 2022.
Article in English | ScienceDirect | ID: covidwho-2158569

ABSTRACT

The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both, drugs, and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.

2.
Viruses ; 14(12):2764, 2022.
Article in English | MDPI | ID: covidwho-2155319

ABSTRACT

The ongoing evolution of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in the recent emergence of a highly divergent variant of concern (VOC) defined as Omicron or B.1.1.529. This VOC is of particular concern because it has the potential to evade most therapeutic antibodies and has undergone a sustained genetic evolution, resulting in the emergence of five distinct sub-lineages. However, the evolutionary dynamics of the initially identified Omicron BA.1 and BA.2 sub-lineages remain poorly understood. Herein, we combined Bayesian phylogenetic analysis, mutational profiling, and selection pressure analysis to track the virus's genetic changes that drive the early evolutionary dynamics of the Omicron. Based on the Omicron dataset chosen for the improved temporal signals and sampled globally between November 2021 and January 2022, the most recent common ancestor (tMRCA) and substitution rates for BA.1 were estimated to be that of 18 September 2021 (95% highest posterior density (HPD), 4 August-22 October 2021) and 1.435 ×10-3 (95% HPD =  1.021 ×10-3 - 1.869 ×10-3) substitution/site/year, respectively, whereas 3 November 2021 (95% highest posterior density (HPD) 26 September-28 November 2021) and 1.074 ×10-3 (95% HPD =  6.444 ×10-4 - 1.586 ×10-3) substitution/site/year were estimated for the BA.2 sub-lineage. The findings of this study suggest that the Omicron BA.1 and BA.2 sub-lineages originated independently and evolved over time. Furthermore, we identified multiple sites in the spike protein undergoing continued diversifying selection that may alter the neutralization profile of BA.1. This study sheds light on the ongoing global genomic surveillance and Bayesian molecular dating analyses to better understand the evolutionary dynamics of the virus and, as a result, mitigate the impact of emerging variants on public health.

3.
Int J Biol Macromol ; 2022 Nov 24.
Article in English | MEDLINE | ID: covidwho-2122503

ABSTRACT

One of the main obstacles in prevention and treatment of COVID-19 is the rapid evolution of the SARS-CoV-2 Spike protein. Given that Spike is the main target of common treatments of COVID-19, mutations occurring at this virulent factor can affect the effectiveness of treatments. The B.1.617.2 lineage of SARS-CoV-2, being characterized by many Spike mutations inside and outside of its receptor-binding domain (RBD), shows high infectivity and relative resistance to existing cures. Here, utilizing a wide range of computational biology approaches, such as immunoinformatics, molecular dynamics (MD), analysis of intrinsically disordered regions (IDRs), protein-protein interaction analyses, residue scanning, and free energy calculations, we examine the structural and biological attributes of the B.1.617.2 Spike protein. Furthermore, the antibody design protocol of Rosetta was implemented for evaluation the stability and affinity improvement of the Bamlanivimab (LY-CoV55) antibody, which is not capable of interactions with the B.1.617.2 Spike. We observed that the detected mutations in the Spike of the B1.617.2 variant of concern can cause extensive structural changes compatible with the described variation in immunogenicity, secondary and tertiary structure, oligomerization potency, Furin cleavability, and drug targetability. Compared to the Spike of Wuhan lineage, the B.1.617.2 Spike is more stable and binds to the Angiotensin-converting enzyme 2 (ACE2) with higher affinity.

4.
Current Research in Structural Biology ; 2022.
Article in English | ScienceDirect | ID: covidwho-2122411

ABSTRACT

SARS-CoV-2 is the infectious agent responsible for the coronavirus disease since 2019, which is the viral pneumonia pandemic worldwide. The structural knowledge on SARS-CoV-2 is rather limited. These limitations are also applicable to one of the most attractive drug targets of SARS-CoV-2 proteins – namely, main protease Mpro, also known as 3C-like protease (3CLpro). This protein is crucial for the processing of the viral polyproteins and plays crucial roles in interfering viral replication and transcription. In fact, although the crystal structure of this protein with an inhibitor was solved, Mpro conformational dynamics in aqueous solution is usually studied by molecular dynamics simulations without special sampling techniques. We conducted replica exchange molecular dynamics simulations on Mpro in water and report the dynamic structures of Mpro in an aqueous environment including root mean square fluctuations, secondary structure properties, radius of gyration, and end-to-end distances, chemical shift values, intrinsic disorder characteristics of Mpro and its active sites with a set of computational tools. The active sites we found coincide with the currently known sites and include a new interface for interaction with a protein partner.

5.
Droplets of Life ; : 681-698, 2023.
Article in English | ScienceDirect | ID: covidwho-2104198

ABSTRACT

Infectious diseases continue to represent a major threat to the humankind. This is reiterated by the current COVID-19 pandemic that affected almost 550 million people worldwide and caused more than 6.35 million deaths. It is clear that in addition to the existing preventive measures and treatments for various pathogens, better understanding is needed of the relationship between pathogen infection and the human antiinfection immune response and of the specific mechanisms underlying these complex processes. There is a constant warfare between the hosts and infectious pathogens, where humans have evolved a very effective and broadly amended antiinfection immune system, but, in their turn, pathogens have evolved a multitude of immune escape mechanisms to efficiently oppose it. It is recognized now that liquid–liquid phase separation (LLPS) occupies a special place among the important molecular mechanisms of the antiinfection immune response. Some illustrative examples of the roles of LLPS in the antiinfection immune response are considered in this chapter.

6.
Curr Pharm Des ; 2022 Oct 24.
Article in English | MEDLINE | ID: covidwho-2089589

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major health concern worldwide and evolved into different variants. SARS-CoV-2 possesses a spike glycoprotein on its envelope that binds to the angiotensin-converting enzyme 2 (ACE-2) receptor of the host cell via the receptor-binding domain (RBD) in the upper respiratory tract. Since the SARS-CoV-2 virus variants changes the seveirity of dieseases and treatment scenarios, repurposing current medicines may provide a quick and appealing method with established safety features. The efficacy and safety of antiviral medicines against the coronavirus disease 2019 (COVID-19) have been investigated, and several of them are now undergoing clinical studies. Recently, it has been found that nitric oxide (NO) shows antiviral properties against SARS-CoV-2 and prevents the virus from binding to a host cell. In addition, NO is a well-known vasodilator and acts as an important coagulation mediator. With the fast-track development of COVID-19 treatments and vaccines, one avenue of research aimed at improving therapeutics is exploring different forms of drug delivery, including intranasal sprays and inhalation therapy. The nasal mucosa is more prone to be the site of infection as it is in more direct contact with the physical environment via air during inhalation and exhalation. Thus, the use of the exogenous nasal NO therapy via the intranasal route displays a distinct advantage. Therefore, the objective of this review is to summarize the relevant actions of NO via intranasal spray and inhalation delivery, its mechanism of action, and its use in the treatment of COVID-19.

7.
Cell Signal ; 101: 110495, 2022 Oct 15.
Article in English | MEDLINE | ID: covidwho-2068757

ABSTRACT

The COVID-19 pandemic has been the focus of research the past two years. The major breakthrough was made by discovering pathways related to SARS-CoV-2 infection through cellular interaction by angiotensin-converting enzyme (ACE2) and cytokine storm. The presence of ACE2 in lungs, intestines, cardiovascular tissues, brain, kidneys, liver, and eyes shows that SARS-CoV-2 may have targeted these organs to further activate intracellular signalling pathways that lead to cytokine release syndrome. It has also been reported that SARS-CoV-2 can hijack coatomer protein-I (COPI) for S protein retrograde trafficking to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), which, in turn, acts as the assembly site for viral progeny. In infected cells, the newly synthesized S protein in endoplasmic reticulum (ER) is transported first to the Golgi body, and then from the Golgi body to the ERGIC compartment resulting in the formation of specific a motif at the C-terminal end. This review summarizes major events of SARS-CoV-2 infection route, immune response following host-cell infection as an important factor for disease outcome, as well as comorbidity issues of various tissues and organs arising due to COVID-19. Investigations on alterations of host-cell machinery and viral interactions with multiple intracellular signaling pathways could represent a major factor in more effective disease management.

8.
Inflammation ; 2022 Oct 10.
Article in English | MEDLINE | ID: covidwho-2059940

ABSTRACT

Hyper-transmissibility with decreased disease severity is a typical characteristic of the SARS-CoV-2 Omicron variant. To understand this phenomenon, we used various bioinformatics approaches to analyze randomly selected genome sequences (one each) of the Gamma, Delta, and Omicron variants submitted to NCBI from December 15 to 31, 2021. We report that the pathogenicity of SARS-CoV-2 variants decreases in the order of Wuhan > Gamma > Delta > Omicron; however, the antigenic property follows the order of Omicron > Gamma > Wuhan > Delta. The Omicron spike RBD shows lower pathogenicity but higher antigenicity than other variants. The reported decreased disease severity by the Omicron variant may be due to its decreased pro-inflammatory and IL-6 stimulation and increased IFN-γ and IL-4 induction efficacy. The mutations in the N protein are probably associated with this decreased IL-6 induction and human DDX21-mediated increased IL-4 production for Omicron. Due to the mutations, the stability of S, M, N, and E proteins decreases in the order of Omicron > Gamma > Delta > Wuhan. Although a stronger spike RBD-hACE2 binding of Omicron increases its transmissibility, the lowest stability of its spike protein makes spike RBD-hACE2 interaction weak for systemic infection and for causing severe disease. Finally, the highest instability of the Omicron E protein may also be associated with decreased viral maturation and low viral load, leading to less severe disease and faster recovery. Our findings will contribute to the understanding of the dynamics of SARS-CoV-2 variants and the management of emerging variants. This minimal genome-based method may be used for other similar viruses avoiding robust analysis.

9.
Biomolecules ; 12(10)2022 09 23.
Article in English | MEDLINE | ID: covidwho-2043570

ABSTRACT

The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID-percentage of intrinsic disorder-of the membrane protein M, PIDM) and higher flexibility of the inner shell (higher PID of the nucleocapsid protein N, PIDN) are correlated with the contagiousness and virulence, respectively. M protects the virion from the anti-microbial enzymes in the saliva and mucus. N disorder is associated with the rapid replication of the virus. SDM predictions are supported by two experimental observations. The first observation demonstrated lesser and greater presence of the Omicron particles in the lungs and bronchial tissues, respectively, as there is a greater level of mucus in the bronchi. The other observation revealed that there are lower viral loads in 2017-pangolin-CoV, which is predicted to have similarly low PIDN as Omicron. The abnormally hard M, which is very rarely seen in coronaviruses, arose from the fecal-oral behaviors of pangolins via exposure to buried feces. Pangolins provide an environment for coronavirus (CoV) attenuation, which is seen in Omicron. Phylogenetic study using M shows that COVID-19-related bat-CoVs from Laos and Omicron are clustered in close proximity to pangolin-CoVs, which suggests the recurrence of interspecies transmissions. Hard M may have implications for long COVID-19, with immune systems having difficulty degrading viral proteins/particles.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Animals , Pangolins , Phylogeny , Reproducibility of Results , Viral Proteins , Nucleocapsid Proteins/genetics , Membrane Proteins
10.
Int J Biol Macromol ; 222(Pt A): 972-993, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2041800

ABSTRACT

Several hypotheses have been presented on the origin of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from its identification as the agent causing the current coronavirus disease 19 (COVID-19) pandemic. So far, no solid evidence has been found to support any hypothesis on the origin of this virus, and the issue continue to resurface over and over again. Here we have unfolded a pattern of distribution of several mutations in the SARS-CoV-2 proteins in 24 geo-locations across different continents. The results showed an evenly uneven distribution of the unique protein variants, distinct mutations, unique frequency of common conserved residues, and mutational residues across these 24 geo-locations. Furthermore, ample mutations were identified in the evolutionarily conserved invariant regions in the SARS-CoV-2 proteins across almost all geo-locations studied. This pattern of mutations potentially breaches the law of evolutionary conserved functional units of the beta-coronavirus genus. These mutations may lead to several novel SARS-CoV-2 variants with a high degree of transmissibility and virulence. A thorough investigation on the origin and characteristics of SARS-CoV-2 needs to be conducted in the interest of science and for the preparation of meeting the challenges of potential future pandemics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/genetics , Pandemics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Mutation
11.
Expert Rev Vaccines ; 21(11): 1603-1620, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1991936

ABSTRACT

INTRODUCTION: Several vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed since the inception of the coronavirus disease 2019 (COVID-19) in December 2019, at unprecedented speed. However, these rapidly developed vaccines raised many questions related to the efficacy and safety of vaccines in different communities across the globe. Various hypotheses regarding COVID-19 and its vaccines were generated, and many of them have also been answered with scientific evidence. Still, there are many myths/misinformation related to COVID-19 and its vaccines, which create hesitancy for COVID-19 vaccination, and must be addressed critically to achieve success in the battle against the pandemic. AREA COVERED: The development of anti-SARS-CoV-2 vaccines against COVID-19, their safety and efficacy, and myths/misinformation relating to COVID-19 and vaccines are presented. EXPERT OPINION: In this pandemic, we have seen a global collaborative effort of researchers, governments, and industry, supported by billions of dollars in funding, have allowed the development of vaccines far more quickly than in the past. Vaccines go through rigorous testing, analysis, and evaluations in clinical settings prior to their approval, even if they are approved for emergency use. Despite the myths, vaccination represents an important strategy to get back to normality.


Subject(s)
COVID-19 , Humans , COVID-19/prevention & control , COVID-19 Vaccines , SARS-CoV-2 , Pandemics/prevention & control , Vaccination
12.
COVID ; 2(8):1089-1101, 2022.
Article in English | MDPI | ID: covidwho-1969118

ABSTRACT

For the first time in history, we have witnessed the origin and development of a pandemic. To handle the accelerated accumulation of viral mutations and to comprehend the virus' evolutionary adaptation in humans, an unparalleled program of genetic sequencing and monitoring of SARS-CoV-2 variants has been undertaken. Several scientists have theorized that, with the Omicron surge producing a more contagious but less severe disease, the end of COVID-19 is near. However, by analyzing the behavior shown by this virus for 2 years, we have noted that pandemic viruses do not always show decreased virulence. Instead, it appears there is an evolutionary equilibrium between transmissibility and virulence. We have termed this concept 'intermittent virulence';. The present work analyzes the temporal and epidemiological behavior of SARS-CoV-2 and suggests that there is a high possibility that new virulent variants will arise in the near future, although it is improbable that SARS-CoV-2's virulence will be the same as was seen during the alpha or delta waves, due to the fact that the human population has reached a sufficient level of herd immunity through natural infection or due to the vaccination programs. The most recent global mortality data raised a question whether this pandemic is really over. Furthermore, it is uncertain when the endemic phase will begin. Darwin's words: 'the survival of the fittest';are still valid, and the virus will continue killing nonvaccinated old people, vaccinated old people, and those with comorbidities. We have underestimated the SARS-CoV-2 mastery of immune escape and have not yet seen the full adaptive potential this virus can develop through natural selection.

13.
Int J Biol Macromol ; 217: 492-505, 2022 Sep 30.
Article in English | MEDLINE | ID: covidwho-1926499

ABSTRACT

Conventional drug development strategies typically use pocket in protein structures as drug-target sites. They overlook the plausible effects of protein evolvability and resistant mutations on protein structure which in turn may impair protein-drug interaction. In this study, we used an integrated evolution and structure guided strategy to develop potential evolutionary-escape resistant therapeutics using receptor binding domain (RBD) of SARS-CoV-2 spike-protein/S-protein as a model. Deploying an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence-space. Guided by molecular simulation and structure network analysis we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility. Using fuzzy C-means clustering we combined evolutionary and structural features of RBD and identified a critical region. Subsequently, we used computational drug screening using a library of 1615 small molecules and identified one lead molecule, which is expected to target the identified region, critical for evolvability and structural stability of RBD. This integrated evolution-structure guided strategy to develop evolutionary-escape resistant lead molecules have potential general applications beyond SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Binding Sites , Humans , Mutation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry
14.
Comput Biol Med ; 147: 105735, 2022 08.
Article in English | MEDLINE | ID: covidwho-1906919

ABSTRACT

Since the new variant of SARS-CoV-2, Omicron (BA.1) has raised serious concerns, it is important to investigate the effects of mutations in the NTD and RBD domains of the spike protein for the development of COVID-19 vaccines. In this study, computational analysis of the Wuhan and Omicron NTDs and RBDs in their unbound and bound states to mAb 4A8 and ACE2 were performed. In addition, the interaction of NTD with antibody and RBD with ACE2 were evaluated in the presence of long glycans. The results show that long glycans at the surface of NTDs can reduce the accessibility of protein epitopes, thereby reducing binding efficiency and neutralizing potency of specific antibodies. Also, our findings indicate that the existence of the long glycans result in increased stability and enhanced affinity of the RBD to ACE2 in the Wuhan and Omicron variant. Key residues that play an important role in increasing the structural stability of the protein were identified using RIN analysis and in the state of interaction with mAb 4A8 and ACE2 through per-residue decomposition analysis. Further, the results of the free energy binding calculation using MM/GBSA method show that the Omicron variant has a higher infectivity than the Wuhan. This study provides a better understanding of the structural changes in the spike protein and can be useful for the development of novel therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , COVID-19 Vaccines , Humans , Mutation , Peptidyl-Dipeptidase A/chemistry , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
15.
Biochem Biophys Res Commun ; 620: 8-14, 2022 09 10.
Article in English | MEDLINE | ID: covidwho-1906791

ABSTRACT

The high mutability of the SARS-CoV-2 virus is a growing concern among scientific communities and health professionals since it brings the effectiveness of repurposed drugs and vaccines for COVID-19 into question. Although the mutational investigation of the Spike protein of the SARS-CoV-2 virus has been confirmed by many different researchers, there is no thorough investigation carried out at the interacting region to reveal the mutational status and its associated severity. All the energetically favorable mutations and their detailed analytical features that could impact the infection severity of the SARS-CoV-2 virus need to be identified. Therefore, we have thoroughly investigated the most important site of the SARS-CoV-2 virus, which is the interface region (Residue 417-505) of the virus Spike that interacts with the human ACE2 receptor. Further, we have utilized molecular dynamic simulation to observe the relative stability of the Spike protein with partner ACE2, as a consequence of these mutations. In our study, we have identified 52 energetically favorable Spike mutations at the interface while binding to ACE2, of which only 36 significantly enhance the stabilization of the Spike-ACE2 complex. The stability order and molecular interactions of these mutations were also identified. The highest stabilizing mutation V503D confirmed in our study is also known for neutralization resistance.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19 Vaccines , Humans , Molecular Dynamics Simulation , Mutation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
16.
Biomedicines ; 10(6)2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1883996

ABSTRACT

Viruses and their hosts have coevolved for a long time. This coevolution places both the pathogen and the human immune system under selective pressure; on the one hand, the immune system has evolved to combat viruses and virally infected cells, while viruses have developed sophisticated mechanisms to escape recognition and destruction by the immune system. SARS-CoV-2, the pathogen that is causing the current COVID-19 pandemic, has shown a remarkable ability to escape antibody neutralization, putting vaccine efficacy at risk. One of the virus's immune evasion strategies is mitochondrial sabotage: by causing reactive oxygen species (ROS) production, mitochondrial physiology is impaired, and the interferon antiviral response is suppressed. Seminal studies have identified an intra-cytoplasmatic pathway for viral infection, which occurs through the construction of tunneling nanotubes (TNTs), hence enhancing infection and avoiding immune surveillance. Another method of evading immune monitoring is the disruption of the antigen presentation. In this scenario, SARS-CoV-2 infection reduces MHC-I molecule expression: SARS-CoV-2's open reading frames (ORF 6 and ORF 8) produce viral proteins that specifically downregulate MHC-I molecules. All of these strategies are also exploited by other viruses to elude immune detection and should be studied in depth to improve the effectiveness of future antiviral treatments. Compared to the Wuhan strain or the Delta variant, Omicron has developed mutations that have impaired its ability to generate syncytia, thus reducing its pathogenicity. Conversely, other mutations have allowed it to escape antibody neutralization and preventing cellular immune recognition, making it the most contagious and evasive variant to date.

17.
Viruses ; 14(5)2022 04 27.
Article in English | MEDLINE | ID: covidwho-1875798

ABSTRACT

Since December 2019, the COVID-19 pandemic, which originated in Wuhan, China, has resulted in over six million deaths worldwide. Millions of people who survived this SARS-CoV-2 infection show a number of post-COVID complications. Although, the comorbid conditions and post-COVID complexities are to some extent well reviewed and known, the impact of COVID-19 on pre-existing congenital anomalies and genetic diseases are only documented in isolated case reports and case series, so far. In the present review, we analyzed the PubMed indexed literature published between December 2019 and January 2022 to understand this relationship from various points of view, such as susceptibility, severity and heritability. Based on our knowledge, this is the first comprehensive review on COVID-19 and its associations with various congenital anomalies and genetic diseases. According to reported studies, some congenital disorders present high-risk for developing severe COVID-19 since these disorders already include some comorbidities related to the structure and function of the respiratory and cardiovascular systems, leading to severe pneumonia. Other congenital disorders rather cause psychological burdens to patients and are not considered high-risk for the development of severe COVID-19 infection.


Subject(s)
COVID-19 , China , Comorbidity , Humans , Pandemics , SARS-CoV-2/genetics
18.
Molecular Simulation ; : 1-10, 2022.
Article in English | Academic Search Complete | ID: covidwho-1860606

ABSTRACT

SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interacts with viral RNA. To date, hundreds of mutations (base substitutions, deletions, and insertions) have been reported in SARS-CoV-2 Nsp1. Despite the relevance of Nsp1, a few studies have been conducted to understand the effect of those mutations on Nsp1 structure and function. In this study, the effects of the most frequent mutations were investigated using molecular dynamics simulations. We found that several mutations profoundly affect the local intrinsic disorder predisposition, with most deletions increasing disorder propensity and replacement mutations inducing variable effects. We found that deletions Δ80–90 and Δ156–158 destabilise the protein structure. For example, the Δ156–158 cause a higher root-mean-square deviation (RMSD) and Rg values than those of the wild-type of SARS-CoV-2 Nsp1. We also found that the SARS-CoV-2 Nsp1 is slightly more disordered than its counterpart from SARS-CoV. A better understanding of the complexity and dynamic nature of interactions between intrinsically disordered segments of Nsp1 and ribosome subunits might help develop novel therapeutic countermeasures against the SARS-CoV-2 variants. [ FROM AUTHOR] Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

19.
Expert Opin Biol Ther ; 22(6): 763-780, 2022 06.
Article in English | MEDLINE | ID: covidwho-1860687

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 529 million people, and today the world is facing different mutant strains of the virus, leading to increased morbidity rates, fatality rates, and surfacing re-infections. Various therapies, such as prophylactic treatments, repurposed drug treatments, convalescent plasma, and polyclonal antibody therapy have been developed to help combat the coronavirus disease 2019 (COVID-19). AREA COVERED: This review article provides insights into the basic aspects of monoclonal antibodies (mAbs) for the therapy of COVID-19, as well as its advancement in terms of clinical trial and current approval status. EXPERT OPINION: Monoclonal antibodies represents the most effective and viable therapy and/or prophylaxis option against COVID-19, and have shown a reduction of the viral load, as well as lowering hospitalizations and death rates. In different countries, various mAbs are undergoing different phases of clinical trials, with a few of them having entered phases III and IV. Due to the soaring number of cases worldwide, the FDA has given emergency approval for the mAb combinations bamlanivimab with etesevimab and casirivimab with imdevimab.


Subject(s)
COVID-19 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/therapeutic use , COVID-19/therapy , Humans , Immunization, Passive , SARS-CoV-2
20.
Nanomaterials (Basel) ; 12(9)2022 May 09.
Article in English | MEDLINE | ID: covidwho-1847388

ABSTRACT

More than 2 years have passed since the SARS-CoV-2 outbreak began, and many challenges that existed at the beginning of this pandemic have been solved. Some countries have been able to overcome this global challenge by relying on vaccines against the virus, and vaccination has begun in many countries. Many of the proposed vaccines have nanoparticles as carriers, and there are different nano-based diagnostic approaches for rapid detection of the virus. In this review article, we briefly examine the biology of SARS-CoV-2, including the structure of the virus and what makes it pathogenic, as well as describe biotechnological methods of vaccine production, and types of the available and published nano-based ideas for overcoming the virus pandemic. Among these issues, various physical and chemical properties of nanoparticles are discussed to evaluate the optimal conditions for the production of the nano-mediated vaccines. At the end, challenges facing the international community and biotechnological answers for future viral attacks are reviewed.

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