Delta Plus Research Articles

Design, optimization and validation of a small cabin for standardized objective measurements of earmuffs and earplugs on artificial head (ATF) according to ISO4869-3

The attenuation of hearing protection devices is currently mainly measured using the REAT (ISO 4869-1) standardized subjective method. However, during the development step, manufacturers need to carry out a numerous tests quickly making the REAT method unsuitable due to its need of a large number of subjects with associated training time and represents a significant cost. As an alternative, the standardized objective method (ISO 4869-3) uses an artificial head (ATF) in a controlled acoustic environment. Delta Plus called on CTTM to provide a test facility compliant with the 4869-3 standard, and designed with reduced dimensions to fit easily into its test laboratory. The presented work describes the steps of design, development and validation of a measuring cabin meeting these requirements. The search for a suitable geometry for the cabin volume is based on numerical modeling using boundary elements. The cabin, built using this initial approach, is then empirically optimized using different types of diffusers to meet sound field homogeneity criteria. Comparisons of measurements made using both subjective (ISO 4869-1) and objective (ISO 4869-3) methods are presented at the end.

Amyloidogenesis of SARS-CoV-2 delta plus and omicron variants receptor-binding domain (RBD): impact of SUMO fusion tag.

The RBD of SARS-CoV-2 mediates viral entry into host cells by binding to the host receptor ACE2. SARS-CoV-2 infection is linked to various health issues resembling amyloid-related problems, persuading us to investigate the amyloidogenicity of the SARS-CoV-2 spike RBD. The FoldAmyloid program was used to assess the amyloidogenic propensities in the RBD of Delta Plus and RBD of the Omicron variant, with and without the SUMO tag. After the expression of RBDs, purification, and dialysis steps were performed, subsequently the ThT assay, FTIR, and TEM were employed to check the RBD ability to form fibrils. The ThT assay, TEM, and FTIR revealed the ability of RBD to self-assemble into β-sheet-rich aggregates (48.4% β-sheet content). Additionally, the presence of the SUMO tag reduced the formation of RBD amyloid-like fibrils. The amyloidogenic potential of Omicron RBD was higher than Delta Plus, according to both in silico and experimental analyses. The SARS-CoV-2 RBD can assemble itself by forming aggregates containing amyloid-like fibrils and the presence of a SUMO tag can significantly decrease the formation of RBD amyloid-like fibrils. In silico analysis suggested that variation in the ThT fluorescence intensity of amyloid accumulations in the two SARS-CoV-2 strains arises from specific mutations in their RBD regions.

Anticoronavirus activity of rhizome of Dryopteris crassirhizoma via multistage targeting of virus entry and viral proteases, Mpro and PLpro

Ethnopharmacological relevanceThe rhizome of Dryopteris crassirhizoma Nakai (Dryopteridaceae, RDC), a traditional East Asian herbal medicine, possesses a broad spectrum of medicinal properties, including anti-inflammatory, anticancer, antibacterial, and antiviral activities. Aim of the studyThis study investigates the 30% ethanolic extract of RDC's antiviral potential against human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its variants infections. Materials and methodsA 30% ethanolic extract of RDC or its components, filixic acid ABA (PubChem CID: 15081408) and dryocrassin ABBA (PubChem CID: 3082025) were treated with Human Coronavirus infection (HCoV-OC43, SARS-CoV-2 and its variants). The base peak chromatogram of RDC was evaluated using UPLC-Q/TOF Mass to identify the RDC, and the quantitative analysis of RDC compounds was performed using LC-MS/MS. A cytopathic effect (CPE) reduction assay, Western blot, immunofluorescence staining of viral protein expression, and qRT-PCR were performed to quantify the viral RNA copy numbers and determine the antiviral activity. The time-of-addition assay, the virus attachment, penetration, and virucidal assays, and SARS-CoV-2 Mpro and PLpro activity assay were used to elucidate the mode of action. ResultsRDC exhibited dose-dependent inhibition of HCoV-OC43–induced cytopathic effects, reducing viral RNA copy numbers and viral protein levels. Time-of-addition assays indicated that RDC targets the early stages of the HCoV-OC43 life cycle, inhibiting virion attachment and penetration with virucidal activity. Notably, filixic acid ABA and dryocrassin ABBA, constituents of RDC, reduced HCoV-OC43 viral RNA loads. Furthermore, RDC effectively blocked viral entry in pseudotyped lentivirus assays, involving spike proteins of SARS-CoV-2 Delta plus and South Africa variants, as well as control lentiviral particles expressing vesicular stomatitis virus glycoprotein G. Additionally, RDC demonstrated inhibition of SARS-CoV-2 infection and its variants by targeting viral proteases, namely main protease (Mpro) and papain-like protease (PLpro). ConclusionsThese findings underscore RDC's multistage approach to targeting viral infections by impeding virus entry and inhibiting viral protease activity. Therefore, RDC holds promise as a potent, broad-spectrum anticoronaviral therapeutic agent.

Insights from in silico study of receptor energetics of SARS-CoV-2 variants.

The emergence of new variants of the novel coronavirus SARS-CoV-2 with increased infectivity, superior virulence, high transmissibility, and unmatched immune escape has demonstrated the adaptability and evolutionary fitness of the virus. The subject of relative order of the binding affinity of SARS-CoV-2 variants with the human ACE2 (hACE2) receptor is hotly debated and its resolution has implications for drug design and development. In this work, we have investigated the energetics of the binding of receptor binding domain (RBD) of SARS-CoV-2 variants of concern (VOCs): Beta (B.1.351), Delta (B.1.617.2), Omicron (B.1.1.529), variant of interest (VOI): Kappa (B.1.617.1), and Delta Plus (B.1.617.2.1) variant with the human ACE2 receptor by using the umbrella sampling (US) method. Our work indicates that Delta and Delta Plus variants have greater values of the US binding free energy than Wild-type (WT), whereas Beta, Kappa, and Omicron variants have lower values. Further analysis of hydrogen bonding, salt bridges, non-bonded interaction energy, and contact surface area at the RBD-hACE2 interface establish Delta as the variant with the highest binding affinity among these variants.

An Analysis on Domestic Violence, Depression and Surge of Anger During the COVID-19 Outbreak in India

Covid-19, which is also referred to as Novel Coronavirus Disease, has begun in China and has rapidly crossed multiple national borders and infected people all over the world, where India has been severely affected by this outbreak in almost all sectors; as a result of the threat of the spread of this viral disease, India, at the beginning, has been forced to shut down all general activities and to force a tight lockdown to restrict human interactions. These sudden restrictions and orders have puzzled and affected the common public in many ways, such as emotionally, physically, financially, and career-wise, halting their potential improvements, and have also ruined many people's livelihoods and the rhythm of life in India. Although the process of unlocking has started and successfully implemented, at the time of post lockdown, people were not afraid of the coronavirus at the same time, due to the experiences of facing rapid attacks from new variants such as Delta, Delta Plus, and Omicron, triggered different psychological and social problems in the living society. In this connection, this research paper exclusively focuses on the sudden rise of domestic violence, depression, and surge of anger between people since the virus outbreak in India. This study covers various associated issues as well as views on financial and social issues and government actions to control the spread of the virus when these negative characteristics make the situation more vulnerable. Thus, through the findings and analysis of this paper, it is useful to know the pulse of common people in India and their tactics to handle these situations which also prevents negativity in people because of these crucial circumstances.

Cross-protection and cross-neutralization capacity of ancestral and VOC-matched SARS-CoV-2 adenoviral vector-based vaccines

COVID-19 vaccines were originally designed based on the ancestral Spike protein, but immune escape of emergent Variants of Concern (VOC) jeopardized their efficacy, warranting variant-proof vaccines. Here, we used preclinical rodent models to establish the cross-protective and cross-neutralizing capacity of adenoviral-vectored vaccines expressing VOC-matched Spike. CoroVaxG.3-D.FR, matched to Delta Plus Spike, displayed the highest levels of nAb to the matched VOC and mismatched variants. Cross-protection against viral infection in aged K18-hACE2 mice showed dramatic differences among the different vaccines. While Delta-targeted vaccines fully protected mice from a challenge with Gamma, a Gamma-based vaccine offered only partial protection to Delta challenge. Administration of CorovaxG.3-D.FR in a prime/boost regimen showed that a booster was able to increase the neutralizing capacity of the sera against all variants and fully protect aged K18-hACE2 mice against Omicron BA.1, as a BA.1-targeted vaccine did. The neutralizing capacity of the sera diminished in all cases against Omicron BA.2 and BA.5. Altogether, the data demonstrate that a booster with a vaccine based on an antigenically distant variant, such as Delta or BA.1, has the potential to protect from a wider range of SARS-CoV-2 lineages, although careful surveillance of breakthrough infections will help to evaluate combination vaccines targeting antigenically divergent variants yet to emerge.

Synthesis, docking studies and biological evaluation of 1H-1,2,3-triazole-7-chloroquinoline derivatives against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded enveloped positive RNA virus and the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Chloroquine (CQ), an antimalarial drug, was reported to be active against several viruses including coronaviruses. The mechanism of host cell invasion by SARS-CoV-2 involves the interaction of angiotensin-converting enzyme (ACE2) with receptor-binding domain (RBD) of spike protein (S). The main protease (Mpro/3CLpro) is an attractive drug target due to its vital function in regulation of polyprotein translated from viral RNA. In this study, a series of novel quinoline-triazole hybrid compounds was synthesized and subjected to evaluations on their cytotoxicity, interactions with different variants of RBD in SARS-CoV-2 and with 3CLpro enzyme by experimental and computational techniques to identify their ability of counteracting viral infection. The results of bio-layer interferometry showed that quinoline derivative 11 has good interaction with delta plus and omicron RBD variants (KD = 3.46 × 10−5 and 6.38 × 10−5 M) while derivative 1 is the best binder for recent variant omicron (KD = 26.9 µM) among the series. Potent compounds 1–4 and 11 also demonstrated a suppressive effect on 3CLpro activity in a non-dose-dependent manner. Further docking study revealed that these compounds interacted within the same area of RBD, while no correlation was found for 3CLpro. Furthermore, the molecular dynamics simulations were carried out to assess the conformational stability of docked complexes for preliminary verification.

DELTA AND DELTA PLUS VARIANT: A SIMPLE ENLIGHTENMENT

SARS-CoV-2 has given rise to several variants such as Alpha, Beta, Gamma, Delta and Omicron are the major but not all COVID strains (variants) currently creating concern. The strains avoid antibodies response because of change in structure (mutations in genome) and thus cause disease. The most prevalent and infectious variant identified so far is Delta variant. The spike protein's structural alterations, which make it quick and fit, cause the greater occurrence. The Delta Plus variant was recently found as a variant of the Delta. Furthermore, twin variants of the Delta Plus variant are making their way around the world. Inactivated vaccines (59%), viral vectors (67.74%), and mRNA-based vaccines (77.74%) were found to be efficacious against diseases caused by the SARS-CoV-2 virus. Currently, Community immunization is an efficient strategy to stop COVID- 19; if not, it may persist for a long time and continue to wreak havoc on humanity

Humoral and Cellular Immune Response Elicited by the BNT162b2 COVID-19 Vaccine Booster in Elderly.

Although the safety and efficacy of COVID-19 vaccines in older people are critical to their success, little is known about their immunogenicity among elderly residents of long-term care facilities (LTCFs). A single-center prospective cohort study was conducted: a total IgG antibody titer, neutralizing antibodies against Wild-type, Delta Plus, and Omicron BA.2 variants and T cell response, were measured eight months after the second dose of BNT162b2 vaccine (T0) and at least 15 days after the booster (T1). Forty-nine LTCF residents, with a median age of 84.8 ± 10.6 years, were enrolled. Previous COVID-19 infection was documented in 42.9% of the subjects one year before T0. At T1, the IgG titers increased up to 10-fold. This ratio was lower in the subjects with previous COVID-19 infection. At T1, IgG levels were similar in both groups. The neutralizing activity against Omicron BA.2 was significantly lower (65%) than that measured against Wild-type and Delta Plus (90%). A significant increase of T cell-specific immune response was observed after the booster. Frailty, older age, sex, cognitive impairment, and comorbidities did not affect antibody titers or T cell response. In the elderly sample analyzed, the BNT162b2 mRNA COVID-19 vaccine produced immunogenicity regardless of frailty.

Process development for an effective COVID-19 vaccine candidate harboring recombinant SARS-CoV-2 delta plus receptor binding domain produced by Pichia pastoris

Recombinant protein-based SARS-CoV-2 vaccines are needed to fill the vaccine equity gap. Because protein-subunit based vaccines are easier and cheaper to produce and do not require special storage/transportation conditions, they are suitable for low-/middle-income countries. Here, we report our vaccine development studies with the receptor binding domain of the SARS-CoV-2 Delta Plus strain (RBD-DP) which caused increased hospitalizations compared to other variants. First, we expressed RBD-DP in the Pichia pastoris yeast system and upscaled it to a 5-L fermenter for production. After three-step purification, we obtained RBD-DP with > 95% purity from a protein yield of > 1 g/L of supernatant. Several biophysical and biochemical characterizations were performed to confirm its identity, stability, and functionality. Then, it was formulated in different contents with Alum and CpG for mice immunization. After three doses of immunization, IgG titers from sera reached to > 106 and most importantly it showed high T-cell responses which are required for an effective vaccine to prevent severe COVID-19 disease. A live neutralization test was performed with both the Wuhan strain (B.1.1.7) and Delta strain (B.1.617.2) and it showed high neutralization antibody content for both strains. A challenge study with SARS-CoV-2 infected K18-hACE2 transgenic mice showed good immunoprotective activity with no viruses in the lungs and no lung inflammation for all immunized mice.

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine.

To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination. Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. After eight months from the second dose, IgG decreased in both serum (T2GMC: 23,838.5ng/ml; T3GMC: 1473.8ng/ml) and saliva (T2GMC: 12.9ng/ml; T3GMC: 0.3ng/ml). Consistently, serum IgA decreased (T2GMC: 48.6ng/ml; T3GMC: 6.4ng/ml); however, salivary IgA showed a different behaviour and increased (T2GMC: 0.06ng/ml; T3GMC: 0.41ng/ml), indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum (IgG T4GMC: 98,493.9ng/ml; IgA T4GMC: 187.5ng/ml) and saliva (IgG T4GMC: 21.9ng/ml; IgA T4GMC: 0.65ng/ml). Moreover, the booster re-established the neutralizing activity in the serum of all individuals, not only against the Wuhan wild-type antigen (N=50; INH: 91.6%) but also against the variants (Delta INH: 91.3%; Delta Plus INH: 89.8%; Omicron BA.1 INH: 85.1%). By contrast, the salivary neutralizing activity was high against the Wuhan antigen in 72% of individuals (N=36, INH: 62.2%), but decreased against the variants, especially against the Omicron BA.1 variant (Delta N=27, INH: 43.1%; Delta Plus N=24, INH: 35.2%; Omicron BA.1N=4; INH: 4.7%). This was suggestive for a different behaviour of systemic immunity observed in serum with respect to mucosal immunity described in saliva (Wald chi-square test, 3 df of interaction between variants and sample type=308.2, p<0.0001). The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant. This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020), Italy.

SCovNet: A skip connection-based feature union deep learning technique with statistical approach analysis for the detection of COVID-19

Background and ObjectiveThe global population has been heavily impacted by the COVID-19 pandemic of coronavirus. Infections are spreading quickly around the world, and new spikes (Delta, Delta Plus, and Omicron) are still being made. The real-time reverse transcription-polymerase chain reaction (RT-PCR) is the method most often used to find viral RNA in a nasopharyngeal swab. However, these diagnostic approaches require human involvement and consume more time per prediction. Moreover, the existing conventional test mainly suffers from false negatives, so there is a chance for the virus to spread quickly. Therefore, a rapid and early diagnosis of COVID-19 patients is needed to overcome these problems. MethodsExisting approaches based on deep learning for COVID detection are suffering from unbalanced datasets, poor performance, and gradient vanishing problems. A customized skip connection-based network with a feature union approach has been developed in this work to overcome some of the issues mentioned above. Gradient information from chest X-ray (CXR) images to subsequent layers is bypassed through skip connections. In the script’s title, “SCovNet” refers to a skip-connection-based feature union network for detecting COVID-19 in a short notation. The performance of the proposed model was tested with two publicly available CXR image databases, including balanced and unbalanced datasets. ResultsA modified skip connection-based CNN model was suggested for a small unbalanced dataset (Kaggle) and achieved remarkable performance. In addition, the proposed model was also tested with a large GitHub database of CXR images and obtained an overall best accuracy of 98.67% with an impressive low false-negative rate of 0.0074. ConclusionsThe results of the experiments show that the proposed method works better than current methods at finding early signs of COVID-19. As an additional point of interest, we must mention the innovative hierarchical classification strategy provided for this work, which considered both balanced and unbalanced datasets to get the best COVID-19 identification rate.

Replacement dynamics and the pathogenesis of the Alpha, Delta and Omicron variants of SARS-CoV-2.

New SARS-CoV-2 variants causing COVID-19 are a major risk to public health worldwide due to the potential for phenotypic change and increases in pathogenicity, transmissibility and/or vaccine escape. Recognising signatures of new variants in terms of replacing growth and severity are key to informing the public health response. To assess this, we aimed to investigate key time periods in the course of infection, hospitalisation and death, by variant. We linked datasets on contact tracing (Contact Tracing Advisory Service), testing (the Second-Generation Surveillance System) and hospitalisation (the Admitted Patient Care dataset) for the entire length of contact tracing in the England - from March 2020 to March 2022. We modelled, for England, time delay distributions using a Bayesian doubly interval censored modelling approach for the SARS-CoV-2 variants Alpha, Delta, Delta Plus (AY.4.2), Omicron BA.1 and Omicron BA.2. This was conducted for the incubation period, the time from infection to hospitalisation and hospitalisation to death. We further modelled the growth of novel variant replacement using a generalised additive model with a negative binomial error structure and the relationship between incubation period length and the risk of a fatality using a Bernoulli generalised linear model with a logit link. The mean incubation periods for each variant were: Alpha 4.19 (95% credible interval (CrI) 4.13-4.26) days; Delta 3.87 (95% CrI 3.82-3.93) days; Delta Plus 3.92 (95% CrI 3.87-3.98) days; Omicron BA.1 3.67 (95% CrI 3.61-3.72) days and Omicron BA.2 3.48 (95% CrI 3.43-3.53) days. The mean time from infection to hospitalisation was for Alpha 11.31 (95% CrI 11.20-11.41) days, Delta 10.36 (95% CrI 10.26-10.45) days and Omicron BA.1 11.54 (95% CrI 11.38-11.70) days. The mean time from hospitalisation to death was, for Alpha 14.31 (95% CrI 14.00-14.62) days; Delta 12.81 (95% CrI 12.62-13.00) days and Omicron BA.2 16.02 (95% CrI 15.46-16.60) days. The 95th percentile of the incubation periods were: Alpha 11.19 (95% CrI 10.92-11.48) days; Delta 9.97 (95% CrI 9.73-10.21) days; Delta Plus 9.99 (95% CrI 9.78-10.24) days; Omicron BA.1 9.45 (95% CrI 9.23-9.67) days and Omicron BA.2 8.83 (95% CrI 8.62-9.05) days. Shorter incubation periods were associated with greater fatality risk when adjusted for age, sex, variant, vaccination status, vaccination manufacturer and time since last dose with an odds ratio of 0.83 (95% confidence interval 0.82-0.83) (P value < 0.05). Variants of SARS-CoV-2 that have replaced previously dominant variants have had shorter incubation periods. Conversely co-existing variants have had very similar and non-distinct incubation period distributions. Shorter incubation periods reflect generation time advantage, with a reduction in the time to the peak infectious period, and may be a significant factor in novel variant replacing growth. Shorter times for admission to hospital and death were associated with variant severity - the most severe variant, Delta, led to significantly earlier hospitalisation, and death. These measures are likely important for future risk assessment of new variants, and their potential impact on population health.

Green and Regioselective Approach for the Synthesis of 3-Substituted Indole Based 1,2-Dihydropyridine and Azaxanthone Derivatives as a Potential Lead for SARS-CoV-2 and Delta Plus Mutant Virus: DFT and Docking Studies.

Great attempts have been done for the development of novel antiviral compounds against SAR-CoV-2 to end this pandemic situation and save human society. Herewith, we have synthesized 3-substituted indole/2-substituted pyrrole 1,2-dihydropyridine and azaxanthone scaffolds using simple, commercially available starting materials in a one-pot, green, and regioselective manner. Further, the regioselectivity of product formation was confirmed by various studies such as controlled experiments, density functional theory (DFT), Mulliken atomic charge, and electrostatic potential (ESP) surface. In addition, 3-substituted indole 1,2-dihydropyridine was successfully converted into a biologically enriched pharmacophore scaffold, viz., indolylimidazopyridinylbenzofuran scaffold, in excellent yield. Moreover, the synthesized 3-substituted indole 1,2-dihydropyridine/2-substituted pyrroles were analyzed in docking studies for anti-SARS-CoV-2 properties against their main protease (Mpro) and anti-Delta plus properties against their protein of the Delta plus K417N mutant. Further, the drug-likeness prediction was analyzed by the Lipinski rule and other pharmacokinetic properties like absorption, distribution, metabolism, excretion, and toxicity using preADMET prediction. Interestingly, the docking results show that out of 20 synthesized compounds, 5 of them for Mpro of SAR-CoV-2 and 9 of them for 7NX7 spike glycoprotein's A chain of Delta plus K417N show greater binding affinity when compared with remdesivir that is the first to receive FDA approval and is currently used as a potent drug for the treatment of COVID-19. These results suggest that indole/pyrrole substituted 1,2-dihydropyridine derivatives are capable of combating SARS-CoV-2 and its Delta plus mutant.

Effect of Mutations in the SARS-CoV-2 Spike RBD Region of Delta and Delta-Plus Variants on its Interaction with ACE2 Receptor Protein

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has undergone multiple significant mutations since its detection in 2019 in Wuhan, China. The emergence of new SARS-CoV-2 variants that can spread rapidly and undermine vaccine-induced immunity threatens the end of the COVID-19 pandemic. The delta variant (B.1.617.2) that emerged in India challenges efforts to control the COVID-19 pandemic. In addition to Delta, so-called Delta Plus sub-variants (B.1.617.2.1 and B.1.617.2.2) have become a new cause of global concern. Here we compare the interaction profile of RBD of the spike protein of the Delta and Delta-Plus variant of SARS-CoV-2 with the ACE2 receptor. From the molecular dynamics simulation, we observed the spike protein of Delta and Delta-Plus variant of SARS-CoV-2 utilizes unique strategies to have stable binding with ACE2. Using MM-GBSA/MM-PBSA algorithms, we found the binding affinity of spike protein of the Delta- variant-ACE2 complex is indeed high (GBTOT = -39.36 kcal mol-1, PBTOT= -17.52 kcal mol-1) in comparison with spike protein of Delta-Plus variant-ACE2 Complex (GBTOT = -36.83 kcal mol-1, PBTOT = -16.03 kcal mol-1). Stable binding of spike protein to ACE2 is essential for virus entry, and the interactions between them should be understood well for the treatment modalities.

The role of spike protein entry inhibitors in the treatment of mild-to-moderate covid-19 in nonhospitalized patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a deadly pneumonia caused by an enveloped, single-stranded positive-sense RNA (+ssRNA), 29.881 kb betacoronavirus, belonging to the coronaviridae 2B lineage.1 Clinically, about 80% of the patients with Covid-19 develop asymptomatic or mild illness, usually within 12 days, whereas 15-30% progress to severe disease with acute respiratory distress syndrome (ARDS), hypoxaemic respiratory failure, multi-organ failure (MOF), and death.2 Patients with mild or moderate SARD-CoV-2 are individuals who have respiratory symptoms but are not in respiratory distress, and have no multiorgan dysfunction, or other complications of Covid-19 that require hospitalization.3 These patients can easily be treated as outpatients under quarantine. However, these individuals can progress to severe SARS-CoV-2 requiring hospitalization, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) if they are not treated. SARS-CoV-2 gain entry into host cells via its spike protein (S) which attaches to its cognitive receptor angiotensin-converting enzyme 2 (ACE2). Spike protein entry inhibitors (SPIs), such as bamlanivimab-etesevimab, casirivimab plus imdevimab, sotrovimab, and bebtelovimab have the potential to inhibit endocytosis, and replication of SARS-CoV-2 in host cells. However, the evolving mutations of SARS-CoV-2 has led to the emergency of new variants, such as Delta Plus, and Omicron BA.1, BA.1617, and BA.2 which are resistant to bamlanivimab-etesevimab, and casirivimab plus imdevimab. Henceforth, these doublet biologics are no longer used in many countries, including the USA. Sotrovimab and bebtelovimab are potent to most variants of concern, and BA.1, they are recommended for the treatment of non-hospitalized patients with Covid-19 in countries with high prevalence of Omicron BA. 1. However, sotrovimab has lost activity against BA.2, therefore, it is no longer recommended in all the states and territories in the USA. Currently, only bebtelovimab is the recommend SPI for the treatment of non-hospitalized patients in the USA.

Comparison of the unbinding process of RBD-ACE2 complex between SARS-CoV-2 variants (Delta, delta plus, and Lambda): A steered molecular dynamics simulation

ABSTRACT The Delta and Lambda SARS-CoV-2 variants are characterised with the double mutations T478K/L452R, and F490S/L452Q, respectively, in their receptor binding domains (RBDs) of the spike proteins. The Delta Plus variant is one of the Delta variant types with K417N substitution in RBD. Basically, SARS-CoV-2 variants need to bind to Angiotensin-Converting Enzyme 2(ACE2) to enter the host cell. Here, the effects of these mutations were studied on the binding affinity of RBD-ACE2 using steered molecular dynamics (SMD) simulation. According to the results, the rupture force of RBD-ACE2 for the wild type and Delta variant were close to each other, and the minimum and maximum rupture forces occurred in the Delta Plus and Lambda variants, respectively. While T478K and L452R occur adjacent to the RBD binding site and have no major effect on the rupture force of the RBD-ACE2 complex, K417N occurs exactly at the binding site of RBD-ACE2 and causes a decrease in the rupture force for the Delta Plus variant. The results of this study showed that T478K, L452R, and K417N could not justify the infection and transmissibility of the Delta and Delta Plus variants. However, L452Q and F490S were able to affect the binding affinity of the RBD-ACE2 complex.

A Study on the Relationship between the 3-D Structure of Spike Proteins and Infectiousness of SARS-CoV-2 Delta Variant

Since the outbreak of novel coronavirus pneumonia in Wuhan in 2019, the SARS-CoV-2 epidemic has become a hot topic. Over time, SARS-CoV-2 has evolved many variants. The diversity of the 3-D structure of the variant’s proteins resulted in the difference in the binding ability and infectious differences between different virus variants and human angiotensin-converting enzyme 2 (ACE2) receptors. In 2020, an evolutionary analysis of the Delta and Delta Plus variants of SARS-CoV-2 provided a three-dimensional model of the protein of the delta variant. However, it only focused on the delta variant and Delta plus variant themselves and did not compare the delta variant or delta plus variant with the original strain. It is hard to give a direct or apparent reason why the delta variant is more infectious and difficult to cure than the original strain. Therefore, this paper further compared the 3-D structures of homologous trimeric spike glycoproteins (S-proteins) and the receptor-binding domain between the SARS-COV-2 original strain and the SARS-COV-2 delta variant. By observing and analyzing the models of the above proteins in the PyMOL Molecular Graphics System, the reasons for the increase of infectivity of the delta variant can be interpreted in a direct way. This article also focuses on the data of the Indian cases from the JHU database to deeply analyze the relationship between the structure and transmission ability of the SARS-CoV-2 delta variant. Last but not least, the reproductive ability of SARS-CoV-2 can be reflected by the number of NAG (2-acetamido-2-deoxy-beta-D-glucopyranose). Through data analysis and protein structure research, we can better understand the characteristics of the binding of SARS-CoV-2 to the human receptor, thus providing a theoretical basis for accurately predicting virus variation. Through the comparative study of virus structure and infectiousness, this paper will provide a scientific basis for the relevant departments to improve epidemic prevention and improve the public's vigilance against virus variants.

Initial introduction and spread of the SARS-CoV-2 AY.4.2.1 Delta variant in Bulgaria, a genomic insight.

The evolution of the emerging SARS‐CoV‐2 variants carrying mutations in the spike protein raises concerns about the possibility of accelerated transmission in the ever‐evolving COVID‐19 pandemic worldwide. AY.4.2, a sublineage of the Delta variant, was considered a variant under investigation (VUI) and also gained the nickname “Delta Plus,” due to its extra mutations, Y145H and A222V. In this study, using genomic epidemiology, we provide the first insights into the introduction of AY.4.2 in Bulgaria and the AY.4.2.1 sublineage that found larger dissemination only in Bulgaria and the United Kingdom.

Structural aspects of SARS-CoV-2 mutations: Implications to plausible infectivity with ACE-2 using computational modeling approach

Some of the SARS-CoV-2 variants are said to be more infectious than the previous others and are causing panic around the globe. Cases related to Delta plus (δ+) and omicron (ο) variants are on the rise worldwide. This sudden surge warrants an investigation into the reasons for its binding with ACE-2. The present study attempts to find out the structural basis of binding interactions of SARS-CoV-2 mutants based on computational modeling and comparative analysis. In silico strategies including protein-protein docking, mutation analysis, molecular dynamics, and binding energy calculations were used to study the binding of the 'receptor binding domain' (RBD) of the seven ‘variants of concern’ which include Alpha (α), Beta (β), Gamma (γ), Kappa (κ), Delta (δ), Delta plus (δ+) and omicron (ο) with ACE-2 (human angiotensin-converting enzyme-2) and with antibodies. Among all the variants dealt with in this study, Delta plus and omicron were found to be binding more strongly to ACE-2 than others due to inherent mutations and the consequent change in the hydrophilic and hydrophobic environment of the binding site. Furthermore, molecular dynamic (MD) simulations and subsequent MM/PBSA calculations provided useful structural insights into key residues participating in the interaction. Infectivity of a virus could be dependent on the interplay of evading antibodies and simultaneously attaching strongly with the host receptor. A cross-correlation between mutant spike proteins' binding with ACE-2 and antibodies provides a holistic assessment of the binding nature of these mutants vis-à-vis native virus and offers opportunities for designing potential therapeutics against these new mutants. Communicated by Ramaswamy H. Sarma