Journal of proteins and proteomics最新文献

COVID-19 [coronavirus disease 2019] has resulted in over 204,644,849 confirmed cases and over 4,323,139 deaths throughout the world as of 12 August 2021, a total of 4,428,168,759 vaccine doses have been administered. The lack of potentially effective drugs against the virus is making the situation worse and dangerous. Numerous forces are working on finding an effective treatment against the virus but it is believed that a de novo drug would take several months even if huge financial support is provided. The only solution left with is drug repurposing that would not only provide effective therapy with the already used clinical drugs, but also save time and cost of the de novo drug discovery. The initiation of the COVID-19 infection starts with the attachment of spike glycoprotein of SARS-CoV-2 to the host receptor. Hence, the inhibition of the binding of the virus to the host membrane and the entry of the viral particle into the host cell are one of the main therapeutic targets. This paper not only summarizes the structure and the mechanism of spike protein, but the main focus is on the potential covalent spike protein inhibitors.

Klebsiella aerogenes is a multidrug-resistant Gram-negative bacterium that causes nosocomial infections. The organism showed resistance to most of the conventional antibiotics available. Because of the high resistance of the species, the treatment of K. aerogenes is difficult. These species are resistant to third-generation cephalosporins due to the production of chromosomal beta-lactams with cephalosporin activity. The lack of better treatment and the development of therapeutic resistance in hospitals hinders better/new broad-spectrum-based treatment against this pathogen. This study identifies potential drug targets/vaccine candidates through a computational subtractive proteome-driven approach. This method is used to predict proteins that are not homologous to humans and human symbiotic intestinal flora. The resultant proteome of K. aerogenes was further searched for proteins, which are essential, virulent, and determinants of antibiotic/drug resistance. Subsequently, their druggability properties were also studied. The data set was reduced based on its presence in the pathogen-specific metabolic pathways. The subtractive proteome analysis predicted 13 proteins as potential drug targets for K. aerogenes. Furthermore, these target proteins were annotated based on their spectrum of activity, cellular localization, and antigenicity properties, which ensured that they are potent candidates for broad-spectrum antibiotic and vaccine design. The results open up new opportunities for designing and manufacturing powerful antigenic vaccines against K. aerogenes and the detection and release of new and active drugs against K. aerogenes without altering the gut microbiome.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00068-9.

M. tuberculosis proliferates within the macrophages during infection and they are bounded by carbohydrates in the cell wall, called lectins. Despite their surface localization, the studies on exact functions of lectins are unexplored. Hence, in our study, using insilico approaches, 11 potential lectins of Mtb was explored as potential drug targets and vaccine candidates. Initially, a gene interaction network was constructed for the 11 potential lectins and identified its functional partners. A gene ontology analysis was also performed for the 11 mycobacterial lectins along with its functional partners and found most of the proteins are present in the extracellular region of the bacterium and belongs to the PE/PPE family of proteins. Further, molecular docking studies were performed for two of the potential lectins (Rv2075c and Rv1917c). A novel series of quinoxalinone and fucoidan derivatives have been made to dock against these selected lectins. Molecular docking study reveals that quinoxalinone derivatives showed better affinity against Rv2075c, whereas fucoidan derivatives have good binding affinity against Rv1917c. Moreover, the mycobacterial lectins can interact with the host and they are considered as potential vaccine candidates. Hence, immunoinformatics study was carried out for all the 11 potential lectins. B-cell and T-cell binding epitopes were predicted using insilico tools. Further, an immunodominant epitope ¹⁰⁶²SIPAIPLSVEV¹⁰⁷² of Rv1917c was identified, which was predicted to bind B-cell and most of the MHC alleles. Thus, the study has explored that mycobacterial lectins could be potentially used as drug targets and vaccine candidates for tuberculosis treatment.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00065-y.

Coronaviruses are enveloped, non-segmented positive-sense RNA viruses with the largest genome among RNA viruses. Their genome contains a large replicase ORF which encodes nonstructural proteins (NSPs), structural, and accessory genes. NSP15 is a nidoviral RNA uridylate-specific endoribonuclease (NendoU) with C-terminal catalytic domain. The endoribonuclease activity of NSP15 interferes with the innate immune response of the host. Here, we screened Selleckchem Natural product database of the compounds against NSP15, and we found that thymopentin and oleuropein displayed highest binding energies. The binding of these molecules was further validated by molecular dynamic simulations that revealed them as very stable complexes. These drugs might serve as effective counter molecules in the reduction of virulence of this virus; may be more effective if treated in combination with replicase inhibitors. Future validation of both these inhibitors is worth the consideration for patients being treated for COVID-19.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00059-w.

Peptides presented by MHC molecules on the cell surface, or the immunopeptidome, play an important role in the adaptive arm of the immune response. Antigen processing for MHC class I molecules is a ubiquitous pathway present in all nucleated cells which generates and presents peptides of both self and non-self-origin. Peptides with post-translational modifications represent one category of peptides presented by MHC class I molecules. However, owing to the complexity of self-peptides presented by cells, the diversity of peptides with post-translational modifications is not well-studied. In this study, we carried out MHC Class I immunopeptidomics analysis of Loucy T-cell leukemia and A375 malignant melanoma cell line to characterize the diversity of post-translational modifications of MHC class I-bound peptides. Using high resolution mass spectrometry, we identified 25,761 MHC-bound peptides across both cell lines using Bolt and Sequest search engines. The enrichment method was highly specific as ~ 90% of the peptides were of typical length (8-12 amino acids long) and the motifs were expected based on previously reported motifs for MHC I alleles. Among the MHC-bound peptides, we identified phosphorylation as a major post-translational modification followed by deamidation. We observed site-specific localization of these post-translational modifications, at position P4 for phosphorylated peptides and position P3 for deamidated peptides. We identified a smaller number of peptides with acetylated and methylated lysine, possibly due to very low stoichiometric levels of these PTMs compared to phosphorylation and deamidation. Using PEAKS de novo sequencing algorithm, we identified spliced peptides that accounted for ~ 5-7% of MHC-bound peptides that were otherwise similar in their features as normal MHC-bound peptides. We validated the identity of several post-translationally modified peptides and spliced peptides through mass spectrometric analysis of synthetic peptides. Our study confirms post-translationally modified peptides to be present at low stoichiometric levels along with unusual spliced peptides through unbiased identification using high resolution mass spectrometry.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00066-x.

COVID-19, the current global pandemic has caused immense damage to human lives and the global economy. It is instigated by the SARS-CoV-2 virus and there is an immediate need for the identification of effective drugs against this deadly virus. SARS-CoV-2 genome codes for four structural proteins, sixteen non-structural proteins (NSPs) and several accessory proteins for its survival inside the host cells. In the present study, through in silico approaches, we aim to identify compounds that are effective against the four NSPs namely, NSP1, NSP4, NSP6 and NSP13 of SARS-CoV-2. The selection criteria of these four NSP proteins are they are least explored and potential targets. First, we have modeled the 3D structures of these proteins using homology modeling methods. Further, through molecular docking studies, we have screened the FDA-approved compounds against these modeled proteins and reported their docking scores. To gain dynamic insights, molecular dynamics studies have also been carried out for the best scored ligand against the NSPs. This study can further pave way for exposing more number of compounds against these proteins and enhance COVID-19 treatment.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00067-w.

The emergence of novel coronavirus SARS-CoV-2 is responsible for causing coronavirus disease-19 (COVID-19) imposing serious threat to global public health. Infection of SARS-CoV-2 to the host cell is characterized by direct translation of positive single stranded (+ ss) RNA to form large polyprotein polymerase 1ab (pp1ab), which acts as precursor for a number of nonstructural and structural proteins that play vital roles in replication of viral genome and biosynthesis of new virus particles. The maintenance of viral protein homeostasis is essential for continuation of viral life cycle in the host cell. To test whether the protein homeostasis of SARS-CoV-2 can be disrupted by inducing specific protein aggregation, we made an effort to examine whether the viral proteome contains any aggregation prone regions (APRs) that can be explored for inducing toxic protein aggregation specifically in viral proteins and without affecting the host cell. This curiosity leads to the identification of several (> 70) potential APRs in SARS-CoV-2 proteome. The length of the APRs ranges from 5 to 25 amino acid residues. Nearly 70% of total APRs investigated are relatively smaller and found to be in the range of 5-10 amino acids. The maximum number of ARPs (> 50) was observed in pp1ab. On the other hand, the structural proteins such as, spike (S), nucleoprotein (N), membrane (M) and envelope (E) proteins also possess APRs in their primary structures which altogether constitute 30% of the total APRs identified. Our findings may provide new windows of opportunities to design specific peptide-based, anti-SARS-CoV-2 therapeutic molecules against COVID-19.

Outbreak of COVID-19 by SARS-CoV-2 infection caused severe acute respiratory syndrome that has been declared a public health emergency of international concern. To control infections, there is urgent need to develop an effective therapeutic strategy. COVID-19 viral spike glycoprotein and proteases play major role in viral entry and mediating virus replication and spread and thus can serve as potential antiviral drug target. Being highly specific, efficacious and safe, peptides hold their place in therapeutics. In present study, molecular docking of 21 pharmacologically active non ribosomal peptides (NRPs) from marine microbes with SARS-CoV-2 spike glycoprotein and papain such as protease was done. Dactinomycin, Tyrocidine A and Gramicidin S showed highest binding interaction with target proteins. The binding affinity of Dactinomycin and Gramicidin S docked with SARS-CoV-2 spike glycoprotein was - 12.4 kcal/mol and - 11.4 kcal/mol, respectively. This suggested their potential to destabilize SARS spike protein binding with human host ACE2 receptor and thus hindering viral entry to the cells. Binding affinity of Tyrocidine A and Gramicidin S with SARS-CoV-2 papain-like protease was - 13.1 kcal/mol and - 11.4 kcal/mol, respectively which might be inhibited COVID-19 by acting on the protease. Gramicidin S showed same binding affinity for both target proteins and thus expected to be most potent. Based on the binding energy score, it was suggested that these pharmacologically active NRPs are potential molecules to be tested against SARS-CoV-2 and used to develop effective antiviral drugs.

There are three types of proteins in coronaviruses: nonstructural, structural, and accessory proteins. Coronavirus proteins are essential for viral replication and for the binding and invasion of hosts and the regulation of host cell metabolism and immunity. This study investigated the amino acid sequence similarity and identity percentages of 10 proteins in SARS-CoV-2, SARS-CoV and the Rhinolophus affinis bat coronavirus (BatCoV RaTG13). The investigated proteins were the 1ab polyprotein, spike protein, orf3a, the envelope protein, the membrane protein, orf6, orf7a, orf7b, orf8, and the nucleocapsid protein. The online sequence alignment service of The European Molecular Biology Open Software Suite (EMBOSS) was used to determine the percentages of protein similarity and identity in the three viruses. The results showed that the similarity and identity percentages of the SARS-CoV-2 and BatCoV RaTG13 proteins were both greater than 95%, while the identity and similarity percentages of SARS-CoV-2 and SARS-CoV were both greater than 38%. The proteins of SARS-CoV-2 and BatCoV RaTG13 have high identity and similarity compared to those of SARS-CoV-2 and SARS-CoV.

Graphic abstract: The proteins of the SARS-CoV-2 are most identical and similar to those of BatCoV RaTG13 than to the proteins of SARS-CoV.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-021-00060-3.