ABSTRACT
Studying viral-host protein-protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2-human protein-protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human-virus interactions and provides hits for further research on COVID-19 therapeutics.
ABSTRACT
This study analyzes the economic impact caused by the COVID-19 pandemic on leisure tourism in Peru, in terms of tourist services such as means of transportation, accommodation, city tours and restaurants. The analysis is based on the application of a survey. The cross-sectional analytical study evaluated 2,443 potential tourists of legal age from the 25 regions of Peru who intended to engage in leisure tourism during the quarantine period. Likewise, potential tourists who intended to make a trip culminating the quarantine (in the remaining time of the year 2020) were evaluated. Based on the study of people who were going to carry out local leisure tourism until the end of 2020, the estimated losses in tourist services amounted to approximately $203 dollars millions (based on a budget less than or equal to $83.00, the amount that most respondents were willing to pay for tourist services). An increase in the demand for domestic leisure tourism is expected associated with the reduction in prices of each tourist service in order to reactivate this sector economically. © 2022 The Author(s). Published by Vilnius Gediminas Technical University.
ABSTRACT
Physical interactions between viral and host proteins are responsible for almost all aspects of the viral life cycle and the host’s immune response. Studying viral-host protein-protein interactions is thus crucial for identifying strategies for treatment and prevention of viral infection. Here, we use high-throughput yeast two-hybrid and affinity purification followed by mass spectrometry to generate a comprehensive SARS-CoV-2-human protein-protein interactome network consisting of both binary and co-complex interactions. We report a total of 739 high-confidence interactions, showing the highest overlap of interaction partners among published datasets as well as the highest overlap with genes differentially expressed in samples (such as upper airway and bronchial epithelial cells) from patients with SARS-CoV-2 infection. Showcasing the utility of our network, we describe a novel interaction between the viral accessory protein ORF3a and the host zinc finger transcription factor ZNF579 to illustrate a SARS-CoV-2 factor mediating a direct impact on host transcription. Leveraging our interactome, we performed network-based drug screens for over 2,900 FDA-approved/investigational drugs and obtained a curated list of 23 drugs that had significant network proximities to SARS-CoV-2 host factors, one of which, carvedilol, showed promising antiviral properties. We performed electronic health record-based validation using two independent large-scale, longitudinal COVID-19 patient databases and found that carvedilol usage was associated with a significantly lowered probability (17%-20%, P < 0.001) of obtaining a SARS-CoV-2 positive test after adjusting various confounding factors. Carvedilol additionally showed anti-viral activity against SARS-CoV-2 in a human lung epithelial cell line [half maximal effective concentration (EC50) value of 4.1 µM], suggesting a mechanism for its beneficial effect in COVID-19. Our study demonstrates the value of large-scale network systems biology approaches for extracting biological insight from complex biological processes.
Subject(s)
COVID-19ABSTRACT
The crescent evolution of a global pandemic COVID-19 and its respiratory syndrome (SARS-Cov-2) has been a constant concern (Ghosh 2021; Khan et al. 2021; Alazmi and Motwalli 2020; Vargas et al. 2020). The absence of a proven and effective medication has compelled all the scientific community to search for a new drug. The use of known drugs is a faster way to develop new therapies. Molecular docking is a powerful tool (Gao et al. J Mol Model 10: 44-54, 2004; Singh et al. J Mol Model 18: 39-51, 2012; Schulz-Gasch and Stahl J Mol Model 9:47-57, 2003) to study the interaction of potential drugs with SARS-CoV-2, Alsalme et al. (2020) and Sanders et al. (2020) spike protein as a consequence the main goal of this article is to present the result of the study of an interaction between (R and S)-Linezolid with receptor-binding domain (RBD) of SARS-Cov-2 spike protein complexed with human Angiostensin-converting enzyme 2 (ACE2) (6vW1 - from PDB). The Linezolid enantiomers were optimized at B3LYP/6-311++G(2d,p) level of theory. Molecular docking of the system (S)-Linezolidâ¯RBDâ¯ACE2 and (R)-Linezolidâ¯RBDâ¯ACE2 was performed, the analysis was made using LigPlot+ and NCIplot software packages, to understand the intermolecular interactions. The UV-Vis and ECD of the complexes - (R and S)-Linezolidâ¯RBDâ¯ACE2 were performed in two layers with DFT/6-311++G(3df,2p) and DFT/6-31G(d), respectively. The results showed that only the (S)-Linezolid had a stable interaction with - 8.05 kcal.mol- 1, whereas all the R-enantiomeric configurations had positive values of binding energy. The (S)-Linezolid had the same interactions as in the (S)-Linezolid ⯠Haluarcula morismortui Ribosomal system, where it is well-known the fact that the latter has biological activity. A specific interaction on the fluorine ring justified an attenuation on the ECD signal, in comparison to isolated species. Therefore, some biological activity of (S)-Linezolid with SARS-CoV-2 RBD was expected, indicated by the modification of its ECD signal and justified by a similar interaction in the S-Linezolidâ¯Haluarcula marismortui Ribosomal system.