Nanotechnology can provide therapeutic agent by targeting molecular structures of SARS-CoV-2 (COVID-19): A Mini-Review

2021 ◽  
Vol 18 ◽  
Author(s):  
Sarwar Allah Ditta ◽  
Atif Yaqub ◽  
Fouzia Tanvir
Keyword(s):  
Viral Entry ◽  
Nigella Sativa ◽  
Biological Properties ◽  
Amino Acid Sequences ◽  
Molecular Structures ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Type I ◽  
Active Components ◽  
Biological Origin

: COVID-19 outbreak hit the world worse at the start of 2020, as of December 11, 2020, more than 1.5 million people have died and more than 68.8 million people have been infected globally. SARS-CoV-2 induces mild to severe progressive respiratory pneumonia, leading to failure of different body organs and ultimately death. Hitherto, there are no specific and potential therapeutic agents available against the virus. The spike protein is a type I surface glycoprotein facilitating entry of the virus into the host cell via hACE2 receptors. The two subunits of the spike protein have a polybasic link as cleavage site (PRAR) in SARS-CoV-2, with additional attachment of O-linked glycans. SARS-CoV and SARS-CoV-2 have 76.5% similarity in amino acid sequences. The pathogenesis and viral entry of SARS-CoV-2 are different from SARS-CoV, therefore, it is a dire need of the time to develop a target-based treatment. Alternative strategies and multidisciplinary research approaches are crucial for developing new antiviral and improved therapies against COVID-19. Nanotechnology has opened new horizons for evaluating the biological properties and efficacy of different materials having biological origin, such as Nigella sativa. It contains various active components such as thymoquinone, thymol, thymohydroquinone, and dithymoquinone with different biological potentials. Metallic nanomaterials have been reported to exhibit antiviral activities against various strains. Understanding molecular interactions and modifying the surface properties of nanomaterials with optimum activity may result in the development of novel antiviral therapies.

Covid-19 Mutations and How the Vaccine Enhances Immune Intelligence

2021 ◽  
Author(s):  
Xanya Sofra
Keyword(s):  
Amino Acid ◽  
Viral Entry ◽  
Open Reading Frames ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Immune Memory ◽  
Type I ◽  
Specific Amino Acid ◽  
Adaptive Efficiency ◽  
Acid Exchange

We traced the coronavirus classification and evolution, analyzed the Covid-19 composition and its distinguishing characteristics when compared to SARS-CoV and MERS-CoV. Despite their close kinship, SARS-CoV and Covid-19 display significant structural differences, including 380 amino acid substitutions, and variable homology between certain open reading frames that are bound to diversify the pathogenesis and virulence of the two viral compounds. A single amino acid substitution such as replacing Aspartate (D) with Glycine (G) composes the D614G mutation that is around 20% more infectious than its predecessor 614D. The B117 variant, that exhibits a 70% transmissibility rate, harbours 23 mutants, each reflecting one amino acid exchange. We examined several globally spreading mutations, 501.V2, B1351, P1, and others, with respect to the specific amino acid conversions involved. Unlike previous versions of coronavirus, where random mutations eventually precipitate extinction, the multiplicity of over 300,000 mutations appears to have rendered Covid-19 more contagious, facilitating its ability to evade detection, thus challenging the effectiveness of a large variety of emerging vaccines. Vaccination enhances immune memory and intelligence to combat or obstruct viral entry by generating antibodies that will prohibit the cellular binding and fusion with the Spike protein, ultimately debilitating the virus from releasing its contents into the cell. Developing antibodies during the innate response, appears to be the most compelling solution in light of the hypothesis that Covid-19 inhibits the production of Interferon type I, compromising adaptive efficiency to recognize the virus, possibly provoking a cytokine storm that injures vital organs. With respect to that perspective, the safety and effectiveness of different vaccines is evaluated and compared, including the Spike protein mRNA version, the Adenovirus DNA, Spike protein subunits, the deactivated virus genres, or, finally, the live attenuated coronavirus that appears to demonstrate the greatest effectiveness, yet, encompass a relatively higher risk.

scholarly journals Virtual Screening of Curcumin and Its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV

2020 ◽  
Author(s):  
Ashish Patel ◽  
Malathi Rajendran ◽  
Suresh B Pakala ◽  
Ashish Shah ◽  
Harnisha Patel ◽  
...  
Keyword(s):  
Binding Energy ◽  
Viral Entry ◽  
Curcuma Longa ◽  
Docking Studies ◽  
Binding Energies ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Pharmacokinetic Parameters ◽  
Angiotensin Converting Enzyme 2 ◽  
Potential Inhibitors

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74 % identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. Potential inhibitors of SARS-CoV and SARS-CoV-2 Spike proteins was determined using molecular docking studies. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -14.18 to -4.04 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-desmethoxycurcumin with: ΔG = -14.18 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors.<br>

scholarly journals The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Helena Winstone ◽  
Maria Jose Lista ◽  
Alisha C. Reid ◽  
Clement Bouton ◽  
Suzanne Pickering ◽  
...  
Keyword(s):  
Viral Entry ◽  
Cleavage Site ◽  
Type I Interferons ◽  
Spike Protein ◽  
Type I ◽  
Furin Cleavage ◽  
Independent Manner ◽  
Type I Ifns ◽  
Furin Cleavage Site ◽  
Potent Inhibition

ABSTRACT The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the spike precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons (IFNs) and, more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2, rather than IFITM3, and the degree of this restriction is governed by route of viral entry. Importantly, removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH and cathepsin dependent in late endosomes, where, like SARS-CoV-1 spike, it is more sensitive to IFITM2 restriction. Furthermore, we found that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests that therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 spike may reduce viral replication through the activity of type I IFNs. IMPORTANCE The furin cleavage site in the spike protein is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals, compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here, we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2 and that the sensitivity is exacerbated by deletion of the furin cleavage site, which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest that one role of the furin cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus, it may represent a potential therapeutic target for COVID-19 treatment development.

scholarly journals Virtual Screening of Curcumin and Its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV

2020 ◽  
Author(s):  
Ashish Patel ◽  
Malathi Rajendran ◽  
Suresh B Pakala ◽  
Ashish Shah ◽  
Harnisha Patel ◽  
...  
Keyword(s):  
Binding Energy ◽  
Viral Entry ◽  
Curcuma Longa ◽  
Binding Energies ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74 % identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. The crystal structure of the SARS-CoV (6CRV: full length S protein) and SARS-CoV-2 Spike proteins (6M0J: Receptor binding domain, RBD) was used to determine potential small molecule inhibitors. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -10.98 to -5.12 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-demethoxycurcumin with: ΔG = -10.98 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors. However, further research is necessary to investigate the ability of these compounds as viral entry inhibitors.<br>

scholarly journals Molecular Characterization of Small Ruminant Lentiviruses of Subtype A5 Detected in Naturally Infected but Clinically Healthy Goats of Carpathian Breed

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 992
Author(s):  
Monika Olech ◽  
Jacek Kuźmak
Keyword(s):  
Small Ruminant ◽  
Clinical Signs ◽  
Small Ruminants ◽  
Pairwise Comparison ◽  
Biological Properties ◽  
Amino Acid Sequences ◽  
Surface Glycoprotein ◽  
Pathogenic Potential ◽  
Small Ruminant Lentiviruses

Small ruminant lentiviruses (SRLVs) are widespread in sheep and goats in Poland, and several subtypes were identified and molecularly characterized up to date. This is the first study that characterizes the molecular properties of A5 strains of SRLV detected in naturally infected, but clinically healthy, Carpathian goats. Segments from three genomic regions (gag, env, and LTR) were analyzed. Genetic distance, pairwise comparison, and phylogenetic analysis revealed that Polish SRLV A5 sequences are closely related to the Swiss and German A5 sequences suggesting a common origin. The epidemiological linkage was identified particularly between the small ruminants of Germany and Poland. Amino acid sequences of immunodominant regions in CA protein were well-conserved within analyzed strains; however, they showed some remarkable changes like substitution (D) to (E), at position 90 in Major Homology Region (MHR) and (T) to (S), at position 141 in epitope 3. In contrast, aa sequences of surface glycoprotein exhibited the highest variability confirming type-specific variation in SU5 epitope. Two deletions in the U3 region of A5 strains were noted: One (8 nt) located near the 5′ end of the U3 region and the other (29 nt) located in the central region of U3. Additionally, all A5 strains had specific deletion (10 nt) in the R region. Furthermore, we did not find a correlation between copies of the CAAAT motif and clinical manifestation in infected animals. These data showed some remarkable features in the viral genome of A5 strains, which may be related to the attenuated phenotype in vivo, characterized by the lack of any clinical signs in infected goats. Certainly, more studies are required to support the hypothesis that these A5 viruses are of low pathogenicity for goats. We want to focus our future studies on the analysis of the whole genomes of these isolates and their biological properties, as well as on clinicopathological studies of goats infected by A5 SRLV, aiming to clarify the pathogenic potential of these viruses.

scholarly journals Multiple Sites on SARS-CoV-2 Spike Protein are Susceptible to Proteolysis by Cathepsins B, K, L, S, and V

2021 ◽  
Author(s):  
Keval Bollavaram ◽  
Tiffanie H. Leeman ◽  
Maggie W. Lee ◽  
Akhil Kulkarni ◽  
Sophia G. Upshaw ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Viral Entry ◽  
Infection Process ◽  
Amino Acid Sequences ◽  
Spike Protein ◽  
Cleavage Sites ◽  
Docking Analysis ◽  
Computational Platform ◽  
Molecular Docking Analysis

AbstractSARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Proteases are central to the infection process of SARS-CoV-2. Cleavage of the spike protein on the virus’s capsid causes the conformational change that leads to membrane fusion and viral entry into the target cell. Since inhibition of one protease, even the dominant protease like TMPRSS2, may not be sufficient to block SARS-CoV-2 entry into cells, other proteases that may play an activating role and hydrolyze the spike protein must be identified. We identified amino acid sequences in all regions of spike protein, including the S1/S2 region critical for activation and viral entry, that are susceptible to cleavage by furin and cathepsins B, K, L, S, and V using PACMANS, a computational platform that identifies and ranks preferred sites of proteolytic cleavage on substrates, and verified with molecular docking analysis and immunoblotting to determine if binding of these proteases can occur on the spike protein that were identified as possible cleavage sites. Together, this study highlights cathepsins B, K, L, S, and V for consideration in SARS-CoV-2 infection and presents methodologies by which other proteases can be screened to determine a role in viral entry. This highlights additional proteases to be considered in COVID-19 studies, particularly regarding exacerbated damage in inflammatory preconditions where these proteases are generally upregulated.

scholarly journals Covid-19 Mutations and the Effect of Different Vaccines on Immune Memory

2021 ◽  
Vol 3 (1) ◽  
pp. 32
Author(s):  
Xanya Sofra
Keyword(s):  
Amino Acid ◽  
Viral Entry ◽  
Open Reading Frames ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Immune Memory ◽  
Type I ◽  
Specific Amino Acid ◽  
Potential Safety ◽  
Acid Exchange

We traced the coronavirus classification and evolution, analyzed the Covid-19 composition and its distinguishing characteristics when compared to SARS-CoV and MERS-CoV. Despite their close kinship, SARS-CoV and Covid-19 display significant structural differences,including 380 amino acid substitutions, and variable homology between certain open reading frames that are bound to diversify the pathogenesis and virulence of the two viral compounds. A single amino acid substitution such as replacing Aspartate (D) with Glycine (G) composes the D614G mutation that is around 20% more infectious than its predecessor 614D. The B117 variant, that exhibits a 70% transmissibility rate, harbours 23 mutants,each reflecting one amino acid exchange. We examined several globally spreading mutations, 501.V2, B1351, P1, and others, with respect to the specific amino acid conversions involved. Unlike previous versions of coronavirus, where random mutations eventually precipitate extinction, the multiplicity of over 300,000 mutations appears to have rendered Covid-19 more contagious, facilitating its ability to evade detection, thus challenging the effectiveness of a large variety of emerging vaccines. Vaccination enhances immune memory and intelligence to combat or obstruct viral entry by generating antibodies that will prohibit the cellular binding and fusion with the Spike protein, restricting the virus from releasing its contents into the cell. Developing antibodies during the innate response,appears to be the most compelling solution in light of the hypothesis that Covid-19 inhibits the production of Interferon type I, compromising adaptive efficiency to recognize the virus, possibly provoking a cytokine storm that injures vital organs. With respect to that perspective, the potential safety and effectiveness of different vaccines are evaluated and compared,including the Spike protein mRNA version, the Adenovirus DNA, Spike protein subunits, the deactivated virus genres, or, finally, the live attenuated coronavirus that appears to demonstrate the greatest effectiveness, yet,encompass a relatively higher risk.

scholarly journals Virtual Screening of Curcumin and Its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV

2020 ◽  
Author(s):  
Ashish Patel ◽  
Malathi Rajendran ◽  
Suresh B Pakala ◽  
Ashish Shah ◽  
Harnisha Patel ◽  
...  
Keyword(s):  
Binding Energy ◽  
Viral Entry ◽  
Curcuma Longa ◽  
Binding Energies ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74 % identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. The crystal structure of the SARS-CoV (6CRV: full length S protein) and SARS-CoV-2 Spike proteins (6M0J: Receptor binding domain, RBD) was used to determine potential small molecule inhibitors. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -10.98 to -5.12 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-demethoxycurcumin with: ΔG = -10.98 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors. However, further research is necessary to investigate the ability of these compounds as viral entry inhibitors.<br>

1,3-Thiazolidin-4-ones: Biological Potential, History, Synthetic Development and Green Methodologies

2018 ◽  
Vol 15 (8) ◽  
pp. 1109-1123
Author(s):  
Jonas da Silva Santos ◽  
Joel Jones Junior ◽  
Flavia M. da Silva
Keyword(s):  
Quality Of Life ◽  
Green Chemistry ◽  
Functional Group ◽  
Biological Properties ◽  
Structural Theory ◽  
Molecular Structures ◽  
Biological Potential ◽  
Synthetic Methodologies ◽  
Over Time

Background: We present here the synthesis of 1,3-thiazolidin-4-one (1) and its functionalised analogues, such as the classical isosteres, glitazone (1,3-thiazolidine-2,4-dione) (2), rhodanine (2-thioxo-1,3- thiazolidin-4-one) (3) and pseudothiohydantoin (2-imino-1,3-thiazolidin-4-one) (4) started in the midnineteenth century to the present day (1865-2018). Objective: The review focuses on the differences in the representation of the molecular structures discussed here over time since the first discussions about the structural theory by Kekulé, Couper and Butlerov. Moreover, advanced synthesis methodologies have been developed for obtaining these functional group, including green chemistry. We discuss about its structure and stability and we show the great biological potential. Conclusion: The 1,3-thiazolidin-4-one nucleus and functionalised analogues such as glitazones (1,3- thiazolidine-2,4-diones), rhodanines (2-thioxo-1,3-thiazolidin-4-ones) and pseudothiohydantoins (2-imino-1,3- thiazolidine-2-4-ones) have great pharmacological importance, and they are already found in commercial pharmaceuticals. Studies indicate a promising future in the area of medicinal chemistry with potential activities against different diseases. The synthesis of these nuclei started in the mid-nineteenth century (1865), with the first discussions about the structural theory by Kekulé, Couper and Butlerov. The present study has demonstrated the differences in the representations of the molecular structures discussed here over time. Since then, various synthetic methodologies have been developed for obtaining these nuclei, and several studies on their structural and biological properties have been performed. Different studies with regards to the green synthesis of these compounds were also presented here. This is the result of the process of environmental awareness. Additionally, the planet Earth is already showing clear signs of depletion, which is currently decreasing the quality of life.

scholarly journals Phytochemical Characterization of Olea europea Leaf Extracts and Assessment of Their Anti-Microbial and Anti-HSV-1 Activity

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1085
Author(s):  
Ichrak Ben-Amor ◽  
Maria Musarra-Pizzo ◽  
Antonella Smeriglio ◽  
Manuela D’Arrigo ◽  
Rosamaria Pennisi ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Biological Properties ◽  
Leaf Extracts ◽  
Gram Positive Bacteria ◽  
Entry Assay ◽  
Olea Europea ◽  
Hsv 1

Owing to the richness of bioactive compounds, Olea europea leaf extracts exhibit a range of health effects. The present research evaluated the antibacterial and antiviral effect of leaf extracts obtained from Olea europea L. var. sativa (OESA) and Olea europea var. sylvestris (OESY) from Tunisia. LC-DAD-ESI-MS analysis allowed the identification of different compounds that contributed to the observed biological properties. Both OESA and OESY were active against Gram-positive bacteria (MIC values between 7.81 and 15.61 μg/mL and between 15.61 and 31.25 μg/mL against Staphylococcus aureus ATCC 6538 for OESY and OESA, respectively). The antiviral activity against the herpes simplex type 1 (HSV-1) was assessed on Vero cells. The results of cell viability indicated that Olea europea leaf extracts were not toxic to cultured Vero cells. The half maximal cytotoxic concentration (CC50) values for OESA and OESY were 0.2 mg/mL and 0.82 mg/mL, respectively. Furthermore, both a plaque reduction assay and viral entry assay were used to demonstrate the antiviral activity. In conclusion, Olea europea leaf extracts demonstrated a bacteriostatic effect, as well as remarkable antiviral activity, which could provide an alternative treatment against resistant strains.

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