Omicron favors neuropilin1 binding over ACE2: Increased infectivity and available drugs

COVID-19 pandemic is continue with thousands of new cases every day around the world, even then different vaccines have been developed and proven efficacious against SARS-CoV-2. Several know antivirals drugs have been repurposed or tested against SARS-CoV-2 but we still don’t have an effective therapeutic strategy to control this viral infection. Moreover, in the race of finding out an efficient antiviral, excess uses of antiviral drugs developed a selective pressure on the virus that results in the high frequency of mutations and the possible emergence of antiviral drug resistance against SARS-CoV-2. Omicron is a recently emerged, highly mutated variant of SARS-CoV-2, reported for high infectivity. In the present study, we performed molecular docking analysis between available potential antiviral drugs (remdesivir, nirmatrelvir, molnupiravir, EIDD-1931, GS-441524, and favipiravir) and omicron S protein including S protein/ACE2 complex. Our results suggest high infectivity of omicron, however, the known antiviral drugs were found efficacious against omicron variant. Further, to investigate the high infectivity of omicron, we performed a docking experiment between omicron S protein and neuropilin1 (NRP1). Surprisingly, results suggest high affinities with NRP1 than ACE2. Overall, results suggest that omicron favors NRP1 binding over ACE2, the possible reason behind improved infectivity of omicron variant.

Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody: mechanisms for the high infectivity, immune evasion and antibody drug discovery

The Omicron variant of SARS-CoV-2 has rapidly become the dominant infective strain and the focus efforts against the ongoing COVID-19 pandemic. Here we report an extensive set of structures of the Omicron spike trimer by its own or in complex with ACE2 and an anti-Omicron antibody. These structures reveal that most Omicron mutations are located on the surface of the spike protein, which confer stronger ACE2 binding by nearly 10 folds but become inactive epitopes resistant to many therapeutic antibodies. Importantly, both RBD and the closed conformation of the Omicron spike trimer are thermodynamically unstable, with the melting temperature of the Omicron RBD decreased by as much as 7 degree, making the spiker trimer prone to random open conformations. An unusual RBD-RBD interaction in the ACE2-spike complex unique to Omicron is observed to support the open conformation and ACE2 binding, serving the basis for the higher infectivity of Omicron. A broad-spectrum therapeutic antibody JMB2002, which has completed Phase 1 clinical trial, is found to interact with the same two RBDs to inhibit ACE2 binding, in a mode that is distinguished from all previous antibodies, thus providing the structural basis for the potent inhibition of Omicron by this antibody. Together with biochemical data, our structures provide crucial insights into higher infectivity, antibody evasion and inhibition of Omicron.

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein.

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

The Analyses of High Infectivity Mechanism of SARS-CoV-2 and Its Variants

SARS-CoV-2 has high infectivity and some of its variants have higher transmissibility. To explore the high infectivity mechanism, the charge distributions of SARS-CoV, SARS-CoV-2, and variants of concern were calculated through a series of net charge calculation formulas. The results showed that the SARS-CoV-2 spike protein had more positive charges than that of SARS-CoV. Further results showed that the variants had similar but higher positive charges than preexisting SARS-CoV-2. In particular, the Delta variant had the greatest increase in positive charges in S1 resulting in the highest infectivity. In particular, the S1 positive charge increased greatly in the Delta variant. The S1 positive charge increased, and due to the large negative charge of angiotensin-converting enzyme-2 (ACE2), this resulted in a large increase in Coulomb’s force between S1 and ACE2. This finding agrees with the expectation that the positive charges in the spike protein result in more negative charges on SARS-CoV-2 antibodies than that of SARS-CoV. Thus, the infectivity of a novel SARS-CoV-2 variant may be evaluated preliminarily by calculating the charge distribution.

ACE2 enzymatic role in the SARS-CoV-2 activation: a perspective through the evolutionary promiscuity and substrate diversity of enzymes

The SARS-CoV-2 is an RNA B type β-coronavirus that distinguishes itself from previous coronaviruses by its high infectivity and mortality rates. The mechanism of viral entry into the host cell via ACE2 is currently under research. Several proteases have been nominated to activate the virus but identifying the exact enzyme/enzymes is missing. Moreover, recent work suggests that TMPRSS2 cannot be the enzyme to cleave the SARS-CoV-2 spike or that multiple proteases contribute to SARS-CoV-2 activation. The multitude of proteases that have been nominated to activate the virus suggests that the consensual identification of the precise, key enzyme is still missing. In this context, we synthesize the current controversies regarding the putative enzymes involved in SARS-CoV-2 infectivity and analyze whether ACE2 could have unexpected enzymatic roles in this process, besides its acknowledged receptor role. We hypothesize that ACE2 plays an enzymatic role as well in SARS-CoV-2 activation. Understanding the exact roles of ACE2 in COVID-19 is capital for the future design of specific, efficient therapies and deserves dedicated research. Our conviction is therefore not "if", “but” "when" will the researchers start to wonder about what is hidden behind the apparent only role of ACE2 as a receptor for SARS-CoV-2.

Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies

The COVID-19 pandemic created a worldwide debilitating health crisis with the entire humanity suffering from the deleterious effects associated with the high infectivity and mortality rates. While significant evidence is currently available online and targets various aspects of the disease, both inflammatory and noninflammatory kidney manifestations secondary to COVID-19 infection are still largely underrepresented. In this review, we summarized current knowledge about COVID-19-related kidney manifestations, their pathologic mechanisms as well as various pharmacotherapies used to treat patients with COVID-19. We also shed light on the effect of these medications on kidney functions that can further enhance renal damage secondary to the illness.

PCR-Sequencing Approaches to Assess Informative Mutations in SARS-Cov-2 Spike (S) and ORF7, ORF8 and N Genes Characterizing Variants of Concern and Variants of Interest

Background: The high infectivity rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the prolonged duration of coronavirus disease 2019 (COVID-19) pandemics have contributed to the emergence of viral variants endowed with evolutionary advantages, leading to enhanced infectivity. The tracking of these lineages is urgent. However, the need to sequence whole-viral genomes through next-generation sequencing (NGS) represents a barrier hampering the massive identification of these variants. Therefore, in the current study, we developed Sanger-sequencing approaches targeting regions of interest containing vast lineage-defining mutations in the SARS-CoV-2 S gene and ORF8 region, allowing for unambiguous identification of all SARS-CoV-2 variants of concern (VOCs) and of interest (VOIs).Methods and results: Primers were designed for polymerase chain reaction (PCR) and nested-PCR to amplify and sequence samples with a low-viral burden. The primers’ annealing sites conservancy were checked in a large group of sequences. Amplification protocols were standardized, and sequencing reactions were performed in a cohort of samples for validation. The primers were highly efficient and sequencing of the targeted regions matched those generated by NGS in the same samples. The sequencing results allowed for the unambiguous identification of B.1.1.7, P.1 and P.2 samples, and would also allow the identification of B.1.617.2, B.1.351 and B.1.427/B.1.429 lineages, which were absent in our cohort.Conclusion: Implementing Sanger-sequencing-based approaches to identify SARS-CoV-2 lineages may represent an alternative to tracking these variants by more laboratories around the world and providing valuable molecular and epidemiologic information to inform health systems.

A Study on Weak Edge Detection of COVID-19’s CT Images Based on Histogram Equalization and Improved Canny Algorithm

The coronavirus disease 2019 (COVID-19) is a substantial threat to people’s lives and health due to its high infectivity and rapid spread. Computed tomography (CT) scan is one of the important auxiliary methods for the clinical diagnosis of COVID-19. However, CT image lesion edge is normally affected by pixels with uneven grayscale and isolated noise, which makes weak edge detection of the COVID-19 lesion more complicated. In order to solve this problem, an edge detection method is proposed, which combines the histogram equalization and the improved Canny algorithm. Specifically, the histogram equalization is applied to enhance image contrast. In the improved Canny algorithm, the median filter, instead of the Gaussian filter, is used to remove the isolated noise points. The K -means algorithm is applied to separate the image background and edge. And the Canny algorithm is improved continuously by combining the mathematical morphology and the maximum between class variance method (OTSU). On selecting four types of lesion images from COVID-CT date set, MSE, MAE, SNR, and the running time are applied to evaluate the performance of the proposed method. The average values of these evaluation indicators are 1.7322, 7.9010, 57.1241, and 5.4887, respectively. Compared with other three methods, these values indicate that the proposed method achieves better result. The experimental results prove that the proposed algorithm can effectively detect the weak edge of the lesion, which is helpful for the diagnosis of COVID-19.

Modelling COVID-19 Scenarios for the States and Federal Territories of Malaysia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 disease, which has become pandemic since December 2019. In the recent months, among five countries in the Southeast Asia, Malaysia has the highest per-capita daily new cases and daily new deaths. A mathematical modelling approach using a Singular Spectrum Analysis (SSA) technique was used to generate data-driven 30-days ahead forecasts for the number of daily cases in the states and federal territories in Malaysia at four consecutive time points between 27 July 2021 and 26 August 2021. Each forecast was produced using SSA prediction model of the current major trend at each time point. The objective is to understand the transition dynamics of COVID-19 in each state by analysing the direction of change of the major trends during the period of study. The states and federal territories in Malaysia were grouped in four categories based on the nature of the transition. Overall, it was found that the COVID-19 spread has progressed unevenly across states and federal territories. Major regions like Selangor, Kuala Lumpur, Putrajaya and Negeri Sembilan were in Group 3 (fast decrease in infectivity) and Labuan was in Group 4 (possible eradication of infectivity). Other states e.g. Pulau Pinang, Sabah, Sarawak, Kelantan and Johor were categorised in Group 1 (very high infectivity levels) with Perak, Kedah, Pahang, Terengganu and Melaka were classified in Group 2 (high infectivity levels). It is also cautioned that SSA provides a promising avenue for forecasting the transition dynamics of COVID-19; however, the reliability of this technique depends on the availability of good quality data.

Hydroxychloroquine- and Azithromycin-Induced Transient Left-Bundle Branch Block in a Patient with COVID-19

Background: COVID-19 has emerged and rapidly spread worldwide due to the high infectivity of the novel coronavirus. A new regimen consisting of a combination of hydroxychloroquine and azithromycin has been under evaluation for efficacy and side effects, especially cardiotoxicity. Case summary: A 58-year-old man was admitted to the hospital for COVID-19 pneumonia. His initial ECG showed sinus tachycardia. He was started on combination therapy of azithromycin and hydroxychloroquine. After the second dose of hydroxychloroquine and initial dose of azithromycin, his ECG showed complete left-bundle branch block (LBBB). The treatment was stopped, and the patient had no cardiac symptoms. On Day 8 of admission, his repeat ECG showed an absence of LBBB. Discussion: The cumulative dose of hydroxychloroquine observed in patients treated for malaria or systemic diseases is cardiotoxic, and few cases of LBBB, have been reported. It is, however, not known whether the use of azithromycin in association with a small dose of hydroxychloroquine induces transient LBBB.