Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey.
Ontology highlight
ABSTRACT:
SUBMITTER: Calvo-Alvarez E
PROVIDER: S-EPMC9320270 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Emerging and re-emerging viral diseases can create devastating effects on human lives and may also lead to economic crises. The ongoing COVID-19 pandemic due to the novel coronavirus (nCoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, has caused a global public health emergency. To date, the molecular mechanism of transmission of SARS-CoV-2, its clinical manifestations and pathogenesis is not completely understood. The global scientific community has intensified its efforts in understanding the biology of SARS-CoV-2 for development of vaccines and therapeutic interventions to prevent the rapid spread of the virus and to control mortality and morbidity associated with COVID-19. To understand the pathophysiology of SARS-CoV-2, appropriate animal models that mimic the biology of human SARS-CoV-2 infection are urgently needed. In this review, we outline animal models that have been used to study previous human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Importantly, we discuss models that are appropriate for SARS-CoV-2 as well as the advantages and disadvantages of various available methods.
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Project description:Coronaviruses (CoVs) are a group of viruses from the family Coronaviridae that can infect humans and animals, causing mild to severe diseases. The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global threat, urging the development of new therapeutic strategies. Here we present a selection of relevant compounds that have been described from 2005 until now as having in vitro and/or in vivo antiviral activities against human and/or animal CoVs. We also present compounds that have reached clinical trials as well as further discussing the potentiality of other molecules for application in (re)emergent CoVs outbreaks. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential SARS-CoV-2 drug candidates.
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Project description:Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.
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Project description:SARS-CoV-2, a newly emerged and highly pathogenic coronavirus, is identified as the causal agent of Coronavirus Disease (2019) (COVID-19) in the late December 2019, in China. The virus has rapidly spread nationwide and spilled over to the other countries around the globe, resulting in more than 120 million infections and 2.6 million deaths until the time of this review. Unfortunately, there are still no specific drugs available against this disease, and it is very necessary to call upon more scientists to work together to stop a further spread. Hence, the recent progress in the development of drugs may help scientific community quickly understand current research status and further develop new effective drugs. Herein, we summarize the cellular entry and replication process of this virus and discuss the recent development of potential viral based drugs that target bio-macromolecules in different stages of the viral life cycle, especially S protein, 3CLPro, PLPro, RdRp and helicase.
| S-EPMC8437701 | biostudies-literature
Project description:The outbreak of the novel coronavirus severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) respiratory disease, led to a global pandemic with high morbidity and mortality. Despite frenzied efforts in therapeutic development, there are currently no effective drugs for treatment, nor are there vaccines for its prevention. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, is one of the most practical treatment options against the outbreak. In this study, we present a novel strategy for in silico molecular modeling screening for potential drugs that may interact with multiple main proteins of SARS-CoV-2. Targeting multiple viral proteins is a novel drug discovery concept in that it enables the potential drugs to act on different stages of the virus' life cycle, thereby potentially maximizing the drug potency. We screened 2631 US Food and Drug Administration (FDA)-approved small molecules against 4 key proteins of SARS-CoV-2 that are known as attractive targets for antiviral drug development. In total, we identified 29 drugs that could actively interact with 2 or more target proteins, with 5 drugs (avapritinib, bictegravir, ziprasidone, capmatinib, and pexidartinib) being common candidates for all 4 key host proteins and 3 of them possessing the desirable molecular properties. By overlaying docked positions of drug candidates onto individual host proteins, it has been further confirmed that the binding site conformations are conserved. The drugs identified in our screening provide potential guidance for experimental confirmation, such as in vitro molecular assays and in vivo animal testing, as well as incorporation into ongoing clinical studies.
| S-EPMC8014887 | biostudies-literature
Project description:Ongoing emergence of SARS-CoV-2 Omicron subvariants and their rapid worldwide spread pose a threat to public health. From November 2022 to February 2023, newly emerged Omicron subvariants, including BQ.1.1, BF.7, BA.5.2, XBB.1, XBB.1.5, and BN.1.9, became prevalent global strains (>5% global prevalence). These Omicron subvariants are resistant to several therapeutic antibodies. Thus, the antiviral activity of current drugs such as remdesivir, molnupiravir, and nirmatrelvir, which target highly conserved regions of SARS-CoV-2, against newly emerged Omicron subvariants need to be evaluated. We assessed the antiviral efficacy of the drugs using the half-maximal inhibitory concentration (IC50) against human isolates of 23 Omicron subvariants and four former SARS-CoV-2 variants of concern (VOCs) and compared it with the antiviral efficacy of these drugs against the SARS-CoV-2 reference strain (hCoV/Korea/KCDC03/2020). Maximal IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir were 1.9 (BA.2.75.2), 1.2 (B.1.627.2), and 1.4 (BA.2.3), respectively, compared to median IC50 values of the reference strain. Moreover, median IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir against the Omicron variants were 0.96, 0.4, and 0.62, respectively, similar to the 1.02, 0.88, and 0.67, respectively, median IC50-fold changes for previous VOCs. Although K90R and P132H in Nsp 5, and P323L, A529V, G671S, V405F, and ins823D in Nsp 12 mutations were identified, these amino acid substitutions did not affect drug antiviral activity. These results indicate that current antivirals retain antiviral efficacy against newly emerged Omicron subvariants. It is important to continue active surveillance and testing of new variants for drug resistance to enable early identification of drug-resistant strains.
| S-EPMC10118056 | biostudies-literature
Project description:BackgroundWith the diffusion of SARS-CoV-2 around the world, human health is being threatened. As there is no effective vaccine yet, the development of the vaccine is urgently in progress.Materials and methodsImmunoinformatics methods were applied to predict epitopes from the Spike protein through mining literature associated with B- and T-cell epitopes prediction published or preprinted since the outbreak of the virus till June 1, 2020. 3D structure of the Spike protein were obtained (PDB ID: 6VSB) for prediction of discontinuous B-cell epitopes and localization of epitopes in the hotspot regions.ResultsMethods provided by the Immune Epitope Database (IEDB) server were the most frequently used to predict epitopes. Sequence alignment of the epitopes extracted from literature with the Spike protein demonstrated that the epitopes in different studies converged to multiple short hotspot regions. There were three hotspot regions found in RBD of the Spike protein harboring B-cell linear epitopes ('RQIAPGQTGKIADYNYKLPD', 'SYGFQPTNGVGYQ' and 'YAWNRKRISNCVA') predicted to have high antigenicity score. Two T-cell epitopes ('KPFERDISTEIYQ' and 'NYNYLYRLFR') predicted to be highly antigenic in the original studies were discovered in the hotspot region. Toxicity and allergenicity analysis confirmed all the five epitopes are of non-toxin, and four of them are of non-allergen. The five epitopes identified in hotspot regions of RBD were found fully exposed based on the 3D structure of the Spike protein.ConclusionThe five epitopes we discovered from literature mining may be potential candidates for diagnostics and vaccine development against SARS-CoV-2.
| S-EPMC7543752 | biostudies-literature
Project description:SARS-CoV and SARS-CoV-2 have been thought to originate from bats. In this study, we screened pharyngeal and anal swabs from 13 064 bats collected between 2016 and 2021 at 703 locations across China for sarbecoviruses, covering almost all known southern hotspots, and found 146 new bat sarbecoviruses. Phylogenetic analyses of all available sarbecoviruses show that there are three different lineages-L1 as SARS-CoV-related CoVs (SARSr-CoVs), L2 as SARS-CoV-2-related CoVs (SC2r-CoVs) and novel L-R (recombinants of L1 and L2)-present in Rhinolophus pusillus bats, in the mainland of China. Among the 146 sequences, only four are L-Rs. Importantly, none belong in the L2 lineage, indicating that circulation of SC2r-CoVs in China might be very limited. All remaining 142 sequences belong in the L1 lineage, of which YN2020B-G shares the highest overall sequence identity with SARS-CoV (95.8%). The observation suggests endemic circulations of SARSr-CoVs, but not SC2r-CoVs, in bats in China. Geographic analysis of the collection sites in this study, together with all published reports, indicates that SC2r-CoVs may be mainly present in bats of Southeast Asia, including the southern border of Yunnan province, but absent in all other regions within China. In contrast, SARSr-CoVs appear to have broader geographic distribution, with the highest genetic diversity and sequence identity to human sarbecoviruses along the southwest border of China. Our data provide the rationale for further extensive surveys in broader geographical regions within, and beyond, Southeast Asia in order to find the most recent ancestors of human sarbecoviruses.
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Project description: Not available
| S-BSST379 | biostudies-other
Project description:Introduction: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp., commonly referred to as TriTryps, are a group of protozoan parasites that cause important human diseases affecting millions of people belonging to the most vulnerable populations worldwide. Current treatments have limited efficiencies and can cause serious side effects, so there is an urgent need to develop new control strategies. Presently, the identification and prioritization of appropriate targets can be aided by integrative genomic and computational approaches. Methods: In this work, we conducted a genome-wide multidimensional data integration strategy to prioritize drug targets. We included genomic, transcriptomic, metabolic, and protein structural data sources, to delineate candidate proteins with relevant features for target selection in drug development. Results and Discussion: Our final ranked list includes proteins shared by TriTryps and covers a range of biological functions including essential proteins for parasite survival or growth, oxidative stress-related enzymes, virulence factors, and proteins that are exclusive to these parasites. Our strategy found previously described candidates, which validates our approach as well as new proteins that can be attractive targets to consider during the initial steps of drug discovery.
| S-EPMC10115950 | biostudies-literature