Simple Theoretical Criterion for Selection of Natural Compounds with Anti-COVID-19 Activity

A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the leading threat to global health. An effective antiviral could not only help those still vulnerable to the virus but could be a critical treatment if a virus emerges toward evading coronavirus disease 2019 (COVID-19) vaccines. Despite the significant efforts to test already-approved drugs for their potential to kill the virus, researchers found very few actually worked. Methods: The present report uses the electronic molecular descriptors, the quasi-valence number (AQVN), and the electron-ion interaction potential (EIIP), for the analysis of natural compounds with proven therapeutic activity against the COVID-19. Results: Based on the analysis of the electronic properties of natural compounds which are effective against SARS-CoV-2 virus the simple theoretical criterion for the selection of candidate compounds for the treatment of COVID-19 is proposed. Conclusions: The proposed theoretical criterion can be used for the identification and optimization of new lead compounds for the treatment of the COVID-19 disease and for the selection of the food and food supplements which could have a beneficial effect on COVID-19 patients

Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method

A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction

Annotation Of The Functional Impact Of Coding Genetic Variants

Summary. Coding genetic variants can have profound effects on protein function. Computational tools for the prediction of these effects are used to complement and guide experimental biological studies. Phylogenetic analyses that determine the evolutionary relationship among related sequences are commonly used to distinguish between functionally significant and insignificant gene variations. Here, we have reviewed applications of the non-alignment sequence analyses method for phylogenetic analyses, ISTREE. Furthermore, we assessed how an unsupervised ISTREE-d3 method based on the universal d3 measure responds to this task compared to supervised and semi-supervised ISTREE methods that were previously used in two studies. The findings presented here suggest that ISTREE-d3 can efficiently substitute for the corresponding supervised models, given that it is more suitable for automatic applications. In conclusion, the ISTREE-d3 method has a broad biological relevance and represents a promising approach in functional assessment of coding gene variations

Natural autoantibodies in healthy neonatals recognizing a peptide derived from the second conserved region of HIV-1 gp120

Background/Aim. High sera reactivity with a peptide derived from human immunodeficiency virus HIV-I envelope protein gp120, NMI., correlate with non-progressive HIV-1 infection and also may have protective role in breast and prostate cancer. We also detected a low NTM1 reactive antibodies titer in healthy HIV negative sera and showed that antibody levels can be significantly increased with vigorous physical activity. However, the immune system seems to be unresponsive or tolerant to this peptide, implicating that the NTM1 sequence encompasses or overlaps a certain innate immune epitope. The aim of this study was to present evidences that NTM1 binding antibodies are components of innate immune humoral response, by confirming their presence in sera of newborn babies. For this purpose we collected a set of 225 innate antigen sequences reported in the literature and screened it for candidate antigens with the highest sequence and spectral similarity to NTM1 derived from HIV-1 gp120. Methods. Sera from 18 newborns were tested using ELISA, with peptide NTM1. Sequences from innate antigen database were aligned by an EMBOSS Water bioinformatics tool. Results. We identified NTM1 reactive antibodies in sera of HIV negative newborn babies. Further, in order to identify which of already known innate antigens are the most similar to NTM1 peptide we screened innate immune antigen sequence database collected from the literature. This screening revealed that the most similar sequence are ribonucleoproteins RO60, in addition to previously identified N-terminus of vasoactive intestinal peptide. Conclusion. The results of this study confirm the hypothesis that NTM1 recognizing antibodies are a part of humoral innate immune response. Further, computational similarity screening revealed a vasoactive intestinal peptide and RO60 as the most similar sequences and the strongest candidate antigens. In the light of the presented results, it is appealing that testing blood reactivity at birth, with specific innate antigens, particularly a vasoactive intestinal peptide, can reveal the potential to develop- or boost protective immune response in breast and prostate cancer and HIV infection later in life

Identification of hemagglutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor

Background: The novel A/H1N1 influenza virus, which recently emerged in North America is most closely related to North American H1N1/N2 swine viruses. Until the beginning of 2009, North American swine H1N1/N2 viruses have only sporadically infected humans as dead-end hosts. In 2009 the A/H1N1 virus acquired the capacity to spread efficiently by human to human transmission. The novel A/H1N1 influenza virus has struck thousands of people in more than 70 countries and killed more than 140, representing a public health emergency of international concern. Here we have studied properties of hemagglutinin of A/H1N1 which may modulate virus/receptor interaction. Results: Analyses by ISM bioinformatics platform of the HA1 protein of North American swine H1N1/N2 viruses and the new A/H1N1 showed that both groups of viruses differed in conserved characteristics that reflect a distinct propensity of these viruses to undergo a specific interaction with swine or human host proteins or receptors. Swine H1N1/N2 viruses that sporadically infected humans featured both the swine and the human interaction pattern. Substitutions F71S, T128S, E302K, M314L in HA1 of swine H1N1 viruses from North America are identified as critical for the human interaction pattern of A/H1N1 and residues D94, D196 and D274 are predicted to be hotspots for polymorphisms which could increase infectivity of A/H1N1 virus. At least one of these residues has already emerged in the A/H1N1 isolates from Spain, Italy and USA. The domain 286-326 was identified to be involved in virus/receptor interaction. Conclusion: Our results (i) contribute to better understanding of the origin of the novel A/H1N1 influenza virus, (ii) provide a tool for monitoring its molecular evolution (iii) predicts hotspots associated with enhanced infectivity in humans and (iv) identify therapeutic and diagnostic targets for prevention and treatment of A/H1N1 infection

Evolution of 2014/15 H3N2 Influenza Viruses Circulating in US: Consequences for Vaccine Effectiveness and Possible New Pandemic

A key factor in the effectiveness of the seasonal influenza vaccine is its immunological compatibility with the circulating viruses during the season. Here we propose a new bioinformatics approach for analysis of influenza viruses which could be used as an efficient tool for selection of vaccine viruses, assessment of the effectiveness of seasonal influenza vaccines, and prediction of the epidemic/pandemic potential of novel influenza viruses

In silico analysis suggests interaction between Ebola virus and the extracellular matrix

The worst Ebola virus (EV) outbreak in history has hit Liberia, Sierra Leone and Guinea hardest and the trend lines in this crisis are grave, and now represents a global public health threat concern. Limited therapeutic and/or prophylactic options are available for people suffering from Ebola virus disease (EVD) and further complicate the situation. Previous studies suggested that the EV glycoprotein (GP) is the main determinant causing structural damage of endothelial cells that triggers the hemorrhagic diathesis, but molecular mechanisms underlying this phenomenon remains elusive. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of the protein-protein interactions, the interaction of GP with endothelial extracellular matrix (ECM) was investigated. Presented results of this in silico study suggest that Elastin Microfibril Interface Located Proteins (EMILINs) are involved in interaction between GP and ECM. This finding could contribute to a better understanding of EV/endothelium interaction and its role in pathogenesis, prevention and therapy of EVD

Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach

In the currentpandemic,findingan effectivedrugto preventortreatthe infectionis the highestpriority.A rapidand safeapproachto counteractCOVID-19is in silicodrugrepurposing.The SARS-CoV-2PLpropromotesviral replicationand modu-latesthe hostimmunesystem,resultingin inhibitionof thehostantiviralinnateimmuneresponse,and thereforeis anattractivedrugtarget.In this study,we useda combinedinsilicovirtualscreeningfor candidatesfor SARS-CoV-2PLproproteaseinhibitors.We usedthe Informationalspectrummethodappliedfor SmallMoleculesfor searchingthe Drugbankdatabasefollowedby moleculardocking.Afterin silicoscreen-ing of drugspace,we identified44 drugsas potentialSARS-CoV-2PLproinhibitorsthat we proposefor furtherexperimentaltesting.A previous version of this manuscript has been deposited on a preprint server: [https://doi.org/10.33774/chemrxiv-2021-39cd6-v2

Conserved Synthetic Peptides from the Hemagglutinin of Influenza Viruses Induce Broad Humoral and T-Cell Responses in a Pig Model

Outbreaks involving either H5N1 or H1N1 influenza viruses (IV) have recently become an increasing threat to cause potential pandemics. Pigs have an important role in this aspect. As reflected in the 2009 human H1N1 pandemia, they may act as a vehicle for mixing and generating new assortments of viruses potentially pathogenic to animals and humans. Lack of universal vaccines against the highly variable influenza virus forces scientists to continuously design vaccines a la carte, which is an expensive and risky practice overall when dealing with virulent strains. Therefore, we focused our efforts on developing a broadly protective influenza vaccine based on the Informational Spectrum Method (ISM). This theoretical prediction allows the selection of highly conserved peptide sequences from within the hemagglutinin subunit 1 protein (HA1) from either H5 or H1 viruses which are located in the flanking region of the HA binding site and with the potential to elicit broader immune responses than conventional vaccines. Confirming the theoretical predictions, immunization of conventional farm pigs with the synthetic peptides induced humoral responses in every single pig. The fact that the induced antibodies were able to recognize in vitro heterologous influenza viruses such as the pandemic H1N1 virus (pH1N1), two swine influenza field isolates (SwH1N1 and SwH3N2) and a H5N1 highly pathogenic avian virus, confirm the broad recognition of the antibodies induced. Unexpectedly, all pigs also showed T-cell responses that not only recognized the specific peptides, but also the pH1N1 virus. Finally, a partial effect on the kinetics of virus clearance was observed after the intranasal infection with the pH1N1 virus, setting forth the groundwork for the design of peptide-based vaccines against influenza viruses. Further insights into the understanding of the mechanisms involved in the protection afforded will be necessary to optimize future vaccine formulations

Molecular makeup of HIV-1 envelope protein

A broad range of structural, functional, and immunological similarities between HIV-1 gp120 and human proteins, especially those participating in immune responses, highlight gp120 as a pleiotropic protein that can in different ways affect many important functions of the human immune system. Here we described some of these properties of HIV-1 gp120 that represent the main obstacle in the development of effective and safe AIDS vaccine