Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is rapidly acquiring new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Previously, we have reported a Sanger method-based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel non-synonymous mutations in V121D, V843F, A889V, and G1691C positions. Results Using different computational tools, we have found V121D substitution has the potential to destabilize the non-structural protein-1 (NSP-1). NSP-1 inactivates the type-1 interferon-induced antiviral system. Hence, this mutant could be a basis of attenuated vaccines against SARS-CoV-2. V843F, A889V, and G1691C are all located in nonstructural protein-3 (NSP-3). G1691C can decrease the flexibility of the protein. V843F and A889V might change the binding pattern and efficacy of SARS-CoV-2 papain-like protease (PLPro) inhibitor GRL0617. V843F substitution in PLPro was the most prevalent mutation in the clinical samples. This mutation showed a reduced affinity for interferon-stimulated gene-15 protein (ISG-15) and might have an impact on innate immunity and viral spread. However, V843F+A889V double mutant exhibited the same binding affinity as wild type PLPro. A possible reason behind this phenomenon can be that V843F is a conserved residue of PLPro which damaged the protease structure, but A889V, a less conserved residue, presumably neutralized that damage. Conclusions Mutants of NSP-1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro might be targeted to develop better anti-SARS therapeutics. We hope our study will help to get better insides during the development of attenuated vaccine and PLPro inhibitors.
Genetic polymorphisms in DNA damage repair and tumor suppressor genes have been associated with increasing the risk of several types of cancer. Analyses of putative functional single nucleotide polymorphisms (SNP) in such genes can greatly improve human health by guiding choice of therapeutics. In this study, we selected nine genes responsible for various cancer types for gene enrichment analysis and found that BRCA1, ATM, and TP53 were more enriched in connectivity. Therefore, we used different computational algorithms to classify the nonsynonymous SNPs which are deleterious to the structure and/or function of these three proteins. The present study showed that the major pathogenic variants (V1687G and V1736G of BRCA1, I2865T and V2906A of ATM, V216G and L194H of TP53) might have a greater impact on the destabilization of the proteins. To stabilize the high-risk SNPs, we performed mutation site-specific molecular docking analysis and validated using molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) studies. Additionally, SNPs of untranslated regions of these genes affecting miRNA binding were characterized. Hence, this study will assist in developing precision medicines for cancer types related to these polymorphisms.
Streptomyces coelicolor is a gram-positive soil bacterium which is well known for the production of several antibiotics used in various biotechnological applications. But numerous proteins from its genome are considered hypothetical proteins. Therefore, the present study aimed to reveal the functions of a hypothetical protein from the genome of S. coelicolor. Several bioinformatics tools were employed to predict the structure and function of this protein. Sequence similarity was searched through the available bioinformatics databases to find out the homologous protein. The secondary and tertiary structure were predicted and further validated with quality assessment tools. Furthermore, the active site and the interacting proteins were also explored with the utilization of CASTp and STRING server. The hypothetical protein showed the important biological activity having with two functional domain including POD-like_MBL-fold and rhodanese homology domain. The functional annotation exposed that the selected hypothetical protein could show the hydrolase activity. Furthermore, protein-protein interactions of selected hypothetical protein revealed several functional partners those have the significant role for the bacterial survival. At last, the current study depicts that the annotated hypothetical protein is linked with hydrolase activity which might be of great interest to the further research in bacterial genetics.
Coronavirus disease-2019 has become an immense threat to global public health. The causative agent of this disease is a novel zoonotic pathogen called Severe Acute Respiratory Syndrome related Coronavirus-2 (SARS-CoV-2). Since this is a newly evolved pathogen, very limited information is available to develop effective therapeutics against this deadly virus. Although bioinformatics based analysis could be handy to unveil drugs or vaccines against bacteria and fungus, such approaches are hardly seen for acellular viruses. However, in this study we rationally merged several powerful in silico techniques and proposed prospective therapeutics based on available omics data for COVID-19. Through meticulous analysis of conserved regions of 67 SARS-CoV-2 strains, spike and membrane glycoproteins were chosen to develop and propose a chimeric vaccine against this virus. siRNAs were also designed against these glycoprotein genes to silence them. Moreover, six drug compound candidates were suggested to inhibit the conserved RNA-directed RNA polymerase protein. Finally, due to the close relationship of SARS-CoV-2 and SARS-CoV, publicly available gene expression datasets of SARS-CoV were analyzed to identify 13 immunoregulatory genes that might develop interferon based therapy. Our study will quicken the researches among pharmaceuticals, researchers and clinicians to develop rapid therapeutics for controlling this notorious pandemic disease.
As the COVID-19 pandemic continues to ravage across the globe and take millions of lives, worldwide efforts to understand its causative agent, SARS-CoV-2 at the genomic level are also running in full swing. Such studies are providing precious insights about the pathogenesis, evolution, strengths and weaknesses of the virus. As of October 1st, 2020, 323 SARS-CoV-2 genomes have been sequenced across Bangladesh. The current study is aimed at answering some vital questions about these sequences. From our analyses, it was discovered that the majority of the SARS-CoV-2 found in Bangladesh belonged to the lineage B 1.1.25 of GR clade. Dhaka and Chittagong division were the most diverse in terms of SARS-CoV-2 clades while Mymensing was the least. There are more variety of clades in southern parts of Bangladesh than the northern parts. The most commonly found SARS-CoV-2 mutations found in the country were Spike_D614G, NSP12_P323L, N_G204R and N_R203K. Even though no significant pattern of distribution could be drawn between mutations found in Bangladesh and the countries with similar mortality rates and the countries with large Bangladeshi diaspora, to a certain degree they match with those in the UK, Oman, Italy, Greece, South Africa and Russia. Therefore, careful eye should be kept on the performance of vaccines in those countries in the near future as they are likely to work well in Bangladesh if they work well there. Mutational events in Bangladesh were found to increase between April and July, 2020 and decrease since August, 2020. The number of mutations per SARS-CoV-2 virus sample in Bangladesh was calculated to be 6.88 which is lower than the global average of 7.23. The decrease and the lower rate of mutation raise the possibility of a vaccine or drug working sustainably to protect the people. Based on these insights, a clear picture about the ongoing pandemic can be drawn in the context of Bangladesh which will help the country take appropriate measures to combat the virus.
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