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1.
Drug Discov Ther ; 15(6): 281-288, 2021.
Article in English | MEDLINE | ID: covidwho-1622790

ABSTRACT

Coronavirus disease 2019 (COVID-19) has had a significant impact on human health and economic development over the past two years. Therapeutics in combination with vaccines are critical measures to fight the pandemic. The three areas of drug development are blocking the entry of SARS-CoV-2 into cells, suppressing viral replication inside cells, and regulating the immune system, and important advances have recently been made in those areas. Increasing numbers of neutralizing antibodies and small molecules that show promise have been fully approved or authorized for emergency use, resulting in decreased mortality of patients with COVID-19. The use of therapeutics will have a great impact on formulating and revising public policies to control the pandemic. The pace of lifting of restrictions and economic recovery worldwide will also accelerate in the future. Here, the drugs or agents that have attracted considerable attention and that have led to remarkable progress in the fight against COVID-19 are reviewed.


Subject(s)
COVID-19 , Drug Development , Drug Discovery , Humans , Pandemics , SARS-CoV-2
2.
Sci Rep ; 12(1): 263, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1612211

ABSTRACT

Cold Atmospheric Plasma (CAP) and Plasma Activated Media (PAM) are effective against bacteria, fungi, cancer cells, and viruses because they can deliver Reactive Oxygen and Nitrogen Species (RONS) on a living tissue with negligible damage on health cells. The antiviral activity of CAP against SARS-CoV-2 is being investigated, however, the same but of PAM has not been explored despite its potential. In the present study, the capability of Plasma Activated Media (PAM) to inactivate SARS-CoV-2 and PR8 H1N1 influenza virus with negligible damage on healthy cells is demonstrated. PAM acted by both virus detaching and diminished replication. Furthermore, the treatment of A549 lung cells at different times with buffered PAM did not induce interleukin 8 expression, showing that PAM did not induce inflammation. These results open a new research field by using PAM to the development novel treatments for COVID-19, influenza, and other respiratory diseases.


Subject(s)
Antiviral Agents/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Plasma Gases/pharmacology , SARS-CoV-2/drug effects , A549 Cells , COVID-19/drug therapy , Drug Discovery , Humans , Influenza, Human/drug therapy , Reactive Nitrogen Species/pharmacology , Reactive Oxygen Species/pharmacology
3.
Sci Rep ; 12(1): 188, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1612207

ABSTRACT

Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes.


Subject(s)
COVID-19/metabolism , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Protein Interaction Maps , SARS-CoV-2/physiology , COVID-19/complications , COVID-19/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Discovery , Humans , Protein Interaction Maps/drug effects
4.
Phytomedicine ; 96: 153889, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1593530

ABSTRACT

BACKGROUND: Lonicera Linn. belonging to the family Caprifoliaceae, the largest genus in the plant family, includes about more than 200 species, which are mainly distributed in northern Africa, North America, Europe and Asia. Some species of this genus have been usually used in traditional Chinese medicine as well as functional foods, cosmetics and other applications, such as L. japonica Thunb. Bioactive components and pharmacological activities of the genus Lonicera plants have received an increasing interest from the scientific community. Thus, a comprehensive and systematic review on their traditional usage in China, chemical components, and their pharmacological properties of their whole plants, bioactive extracts, and bioactive isolates including partial structure-activity relationships from the genus is indispensable. METHODS: Information on genus Lonicera of this systematic electronic literature search was gathered via the published articles, patents, clinical trials website (https://clinicaltrials.gov/) and several online bibliographic databases (PubMed, Sci Finder, Research Gate, Science Direct, CNKI, Web of Science and Google Scholar). The following keywords were used for the online search: Lonicera, phytochemical composition, Lonicerae japonica, Lonicera review articles, bioactivities of Lonicera, anti-inflammatory, antiviral, antimicrobial, anticancer, hepatoprotective, antioxidant, neuroprotective, anti-diabetic, and clinical trials. This review paper consists of a total of 225 papers covering the Lonicera genus from 1800 to 2021, including research articles, reviews, patents, and book chapters. RESULTS: In this review (1800s-2021), about 420 components from the genus of Lonicera Linn. including 87 flavonoids, 222 terpenoids, 51 organic acids, and other compounds, together with their pharmacological activities including anti-inflammatory, antiviral, antimicrobial, anticancer, hepatoprotective, antioxidant, neuroprotective, antidiabetic, anti-allergic, immunomodulatory effects, and toxicity were summarized. CONCLUSION: The relationship is discussed among their traditional usage, their pharmacological properties, and their chemical components, which indicate the genus Lonicera have a large prospect in terms of new drug exploitation, especially in COVID-19 treatment.


Subject(s)
COVID-19 , Lonicera , COVID-19/drug therapy , Drug Discovery , Ethnopharmacology , Humans , Medicine, Traditional , Phytochemicals/pharmacology , Phytotherapy , Plant Extracts/pharmacology , SARS-CoV-2
5.
J Am Soc Mass Spectrom ; 33(1): 181-188, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1596214

ABSTRACT

Affinity selection-mass spectrometry, which includes magnetic microbead affinity selection-screening (MagMASS), is ideal for the discovery of ligands in complex mixtures that bind to pharmacological targets. Therapeutic agents are needed to prevent or treat COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection of human cells by SARS-CoV-2 involves binding of the virus spike protein subunit 1 (S1) to the human cell receptor angiotensin converting enzyme-2 (ACE2). Like antibodies, small molecules have the potential to block the interaction of the viral S1 protein with human ACE2 and prevent SARS-CoV-2 infection. Therefore, a MagMASS assay was developed for the discovery of ligands to the S1 protein. Unlike previous MagMASS approaches, this new assay used robotics for 5-fold enhancement of throughput and sensitivity. The assay was validated using the SBP-1 peptide, which is identical to the ACE2 amino acid sequence recognized by the S1 protein, and then applied to the discovery of natural ligands from botanical extracts. Small molecule ligands to the S1 protein were discovered in extracts of the licorice species, Glycyrrhiza inflata. In particular, the licorice ligand licochalcone A was identified through dereplication and comparison with standards using HPLC with high-resolution tandem mass spectrometry.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery/methods , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Binding Sites/drug effects , COVID-19/metabolism , Chalcones/chemistry , Chalcones/pharmacology , Drug Evaluation, Preclinical/methods , Fabaceae/chemistry , Humans , Ligands , Mass Spectrometry/methods , Molecular Docking Simulation , Protein Binding/drug effects , SARS-CoV-2/metabolism
6.
Science ; 372(6547): 1169-1175, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1583231

ABSTRACT

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cystathionine gamma-Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydrogen Sulfide/metabolism , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Biofilms , Crystallography, X-Ray , Cystathionine gamma-Lyase/chemistry , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Drug Discovery , Drug Resistance, Bacterial , Drug Synergism , Drug Tolerance , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/enzymology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development
7.
Biomolecules ; 11(12)2021 12 18.
Article in English | MEDLINE | ID: covidwho-1581038

ABSTRACT

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.


Subject(s)
Drug Discovery , Gasotransmitters/pharmacology , Hydrogen Sulfide/pharmacology , Animals , Benzenesulfonates/administration & dosage , Benzenesulfonates/metabolism , Benzenesulfonates/pharmacology , Benzenesulfonates/therapeutic use , Chemistry, Pharmaceutical , Gasotransmitters/administration & dosage , Gasotransmitters/metabolism , Gasotransmitters/therapeutic use , Humans , Hydrogen Sulfide/administration & dosage , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/therapeutic use , Morpholines/administration & dosage , Morpholines/metabolism , Morpholines/pharmacology , Morpholines/therapeutic use , Naproxen/administration & dosage , Naproxen/analogs & derivatives , Naproxen/metabolism , Naproxen/pharmacology , Naproxen/therapeutic use , Organothiophosphorus Compounds/administration & dosage , Organothiophosphorus Compounds/metabolism , Organothiophosphorus Compounds/pharmacology , Organothiophosphorus Compounds/therapeutic use
8.
Biomolecules ; 11(12)2021 12 10.
Article in English | MEDLINE | ID: covidwho-1572360

ABSTRACT

Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.


Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimony/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Chlorides/pharmacology , Indazoles/pharmacology , Organogold Compounds/pharmacology , Organometallic Compounds/pharmacology , Ruthenium Compounds/pharmacology , SARS-CoV-2/drug effects , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Animals , Antimony/chemistry , Antiviral Agents/chemistry , Cell Line , Chlorides/chemistry , Chlorocebus aethiops , Drug Discovery , Humans , Indazoles/chemistry , Organogold Compounds/chemistry , Organometallic Compounds/chemistry , Ruthenium Compounds/chemistry , Vero Cells
9.
Molecules ; 26(24)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572567

ABSTRACT

COVID-19 is the name of the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that occurred in 2019. The virus-host-specific interactions, molecular targets on host cell deaths, and the involved signaling are crucial issues, which become potential targets for treatment. Spike protein, angiotensin-converting enzyme 2 (ACE2), cathepsin L-cysteine peptidase, transmembrane protease serine 2 (TMPRSS2), nonstructural protein 1 (Nsp1), open reading frame 7a (ORF7a), viral main protease (3C-like protease (3CLpro) or Mpro), RNA dependent RNA polymerase (RdRp) (Nsp12), non-structural protein 13 (Nsp13) helicase, and papain-like proteinase (PLpro) are molecules associated with SARS-CoV infection and propagation. SARS-CoV-2 can induce host cell death via five kinds of regulated cell death, i.e., apoptosis, necroptosis, pyroptosis, autophagy, and PANoptosis. The mechanisms of these cell deaths are well established and can be disrupted by synthetic small molecules or natural products. There are a variety of compounds proven to play roles in the cell death inhibition, such as pan-caspase inhibitor (z-VAD-fmk) for apoptosis, necrostatin-1 for necroptosis, MCC950, a potent and specific inhibitor of the NLRP3 inflammasome in pyroptosis, and chloroquine/hydroxychloroquine, which can mitigate the corresponding cell death pathways. However, NF-κB signaling is another critical anti-apoptotic or survival route mediated by SARS-CoV-2. Such signaling promotes viral survival, proliferation, and inflammation by inducing the expression of apoptosis inhibitors such as Bcl-2 and XIAP, as well as cytokines, e.g., TNF. As a result, tiny natural compounds functioning as proteasome inhibitors such as celastrol and curcumin can be used to modify NF-κB signaling, providing a responsible method for treating SARS-CoV-2-infected patients. The natural constituents that aid in inhibiting viral infection, progression, and amplification of coronaviruses are also emphasized, which are in the groups of alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones. Natural constituents derived from medicinal herbs have anti-inflammatory and antiviral properties, as well as inhibitory effects, on the viral life cycle, including viral entry, replication, assembly, and release of COVID-19 virions. The phytochemicals contain a high potential for COVID-19 treatment. As a result, SARS-CoV-2-infected cell death processes and signaling might be of high efficacy for therapeutic targeting effects and yielding encouraging outcomes.


Subject(s)
COVID-19/drug therapy , Cell Death/drug effects , Drug Discovery/methods , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , Amino Acid Chloromethyl Ketones/pharmacology , Antiviral Agents/pharmacology , Apoptosis/drug effects , Furans/pharmacology , Humans , Hydroxychloroquine/pharmacology , Imidazoles/pharmacology , Indenes/pharmacology , Indoles/pharmacology , Necroptosis/drug effects , Phytochemicals/pharmacology , Pyroptosis/drug effects , SARS-CoV-2/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology , Viral Proteins/antagonists & inhibitors
10.
BMC Med Genomics ; 14(1): 226, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1542114

ABSTRACT

BACKGROUND: Higher mortality of COVID-19 patients with lung disease is a formidable challenge for the health care system. Genetic association between COVID-19 and various lung disorders must be understood to comprehend the molecular basis of comorbidity and accelerate drug development. METHODS: Lungs tissue-specific neighborhood network of human targets of SARS-CoV-2 was constructed. This network was integrated with lung diseases to build a disease-gene and disease-disease association network. Network-based toolset was used to identify the overlapping disease modules and drug targets. The functional protein modules were identified using community detection algorithms and biological processes, and pathway enrichment analysis. RESULTS: In total, 141 lung diseases were linked to a neighborhood network of SARS-CoV-2 targets, and 59 lung diseases were found to be topologically overlapped with the COVID-19 module. Topological overlap with various lung disorders allows repurposing of drugs used for these disorders to hit the closely associated COVID-19 module. Further analysis showed that functional protein-protein interaction modules in the lungs, substantially hijacked by SARS-CoV-2, are connected to several lung disorders. FDA-approved targets in the hijacked protein modules were identified and that can be hit by exiting drugs to rescue these modules from virus possession. CONCLUSION: Lung diseases are clustered with COVID-19 in the same network vicinity, indicating the potential threat for patients with respiratory diseases after SARS-CoV-2 infection. Pathobiological similarities between lung diseases and COVID-19 and clinical evidence suggest that shared molecular features are the probable reason for comorbidity. Network-based drug repurposing approaches can be applied to improve the clinical conditions of COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Drug Repositioning , Lung Diseases/epidemiology , Pandemics , SARS-CoV-2 , Algorithms , Antiviral Agents/therapeutic use , COVID-19/genetics , Comorbidity , Drug Discovery , Drug Repositioning/methods , Gene Regulatory Networks/drug effects , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Humans , Lung Diseases/drug therapy , Lung Diseases/genetics , Protein Interaction Maps/drug effects , Protein Interaction Maps/genetics , Systems Biology
11.
Methods Mol Biol ; 2390: 177-190, 2022.
Article in English | MEDLINE | ID: covidwho-1499336

ABSTRACT

We describe an approach to early stage drug discovery that explicitly engages with the complexities of human biology. The combined computational and experimental approach is formulated on a conceptual framework in which network biology is used to bridge between individual molecular entities and the cellular phenotype that emerges when those entities interact in a network. Multiple aspects of early stage discovery are addressed including the data-driven elucidation of biological processes implicated in disease, target identification and validation, phenotypic discovery of active molecules and their mechanism of action, and extraction of genetic target support from human population genetics data. Validation is described via summary of a number of discovery projects and details from a project aimed at COVID-19 disease.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Systems Biology , Animals , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/virology , Host-Pathogen Interactions , Humans , Molecular Structure , Molecular Targeted Therapy , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
12.
Methods Mol Biol ; 2390: 103-112, 2022.
Article in English | MEDLINE | ID: covidwho-1499335

ABSTRACT

The development of vaccines for the treatment of COVID-19 is paving the way for new hope. Despite this, the risk of the virus mutating into a vaccine-resistant variant still persists. As a result, the demand of efficacious drugs to treat COVID-19 is still pertinent. To this end, scientists continue to identify and repurpose marketed drugs for this new disease. Many of these drugs are currently undergoing clinical trials and, so far, only one has been officially approved by FDA. Drug repurposing is a much faster route to the clinic than standard drug development of novel molecules, nevertheless in a pandemic this process is still not fast enough to halt the spread of the virus. Artificial intelligence has already played a large part in hastening the drug discovery process, not only by facilitating the selection of potential drug candidates but also in monitoring the pandemic and enabling faster diagnosis of patients. In this chapter, we focus on the impact and challenges that artificial intelligence has demonstrated thus far with respect to drug repurposing of therapeutics for the treatment of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Artificial Intelligence , COVID-19/drug therapy , Drug Discovery , Drug Repositioning , SARS-CoV-2/drug effects , Animals , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/virology , Host-Pathogen Interactions , Humans , Machine Learning , Molecular Structure , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
13.
Mol Syst Biol ; 17(11): e10396, 2021 11.
Article in English | MEDLINE | ID: covidwho-1488875

ABSTRACT

Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , Host-Pathogen Interactions/drug effects , Proteome/drug effects , SARS-CoV-2/physiology , COVID-19/virology , Drug Repositioning , Humans , Mass Spectrometry , Methotrexate/pharmacology , Proteomics , Virus Replication/drug effects
14.
Molecules ; 26(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488677

ABSTRACT

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.


Subject(s)
Coronavirus 3C Proteases/drug effects , Flavones/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacology , Brassicaceae/metabolism , COVID-19/drug therapy , Chlorocebus aethiops , Chromones/pharmacology , Coronavirus 3C Proteases/metabolism , Drug Discovery/methods , Flavones/metabolism , Flavonoids/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/pharmacology , Protease Inhibitors/chemistry , Quercetin/analogs & derivatives , Quercetin/pharmacology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vero Cells
15.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488616

ABSTRACT

After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.


Subject(s)
COVID-19/drug therapy , Cathepsin L/drug effects , Coronavirus 3C Proteases/drug effects , Leupeptins/chemistry , Leupeptins/pharmacology , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalytic Domain/drug effects , Cathepsin L/chemistry , Coronavirus 3C Proteases/chemistry , Drug Design , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidomimetics , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Virus Replication/drug effects , X-Ray Diffraction
16.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488615

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.


Subject(s)
Biological Products/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/drug effects , Drug Design , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Drug Discovery/methods , Drug Repositioning , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Conformation , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects
17.
J Nat Prod ; 84(11): 3001-3007, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1483081

ABSTRACT

The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus, which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Biological Products/pharmacology , Drug Discovery , Computational Biology , Databases, Chemical , Databases, Protein , Ligands , Mass Spectrometry , Protein Interaction Mapping , SARS-CoV-2/drug effects
18.
Molecules ; 26(20)2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1480884

ABSTRACT

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50 of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.


Subject(s)
Aedes/drug effects , Aedes/virology , Camptothecin/analogs & derivatives , Insecticides/pharmacology , Mosquito Vectors/drug effects , Mosquito Vectors/virology , Aedes/physiology , Animals , Antiviral Agents/pharmacology , Camptothecin/pharmacology , Drug Discovery , Female , High-Throughput Screening Assays , Humans , Insecticide Resistance , Larva/drug effects , Larva/physiology , Motor Activity/drug effects , Pandemics/prevention & control , Topoisomerase I Inhibitors/pharmacology , Vector Borne Diseases/epidemiology , Vector Borne Diseases/prevention & control , Virus Replication/drug effects , Zika Virus/drug effects
19.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1480883

ABSTRACT

Viral infections are among the most complex medical problems and have been a major threat to the economy and global health. Several epidemics and pandemics have occurred due to viruses, which has led to a significant increase in mortality and morbidity rates. Natural products have always been an inspiration and source for new drug development because of their various uses. Among all-natural sources, plant sources are the most dominant for the discovery of new therapeutic agents due to their chemical and structural diversity. Despite the traditional use and potential source for drug development, natural products have gained little attention from large pharmaceutical industries. Several plant extracts and isolated compounds have been extensively studied and explored for antiviral properties against different strains of viruses. In this review, we have compiled antiviral plant extracts and natural products isolated from plants reported since 2015.


Subject(s)
Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Development , Plant Extracts/pharmacology , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Drug Discovery , Flavivirus/drug effects , Hepatitis Viruses/drug effects , Humans , Molecular Structure , Orthomyxoviridae/drug effects , Plant Extracts/chemistry , Simplexvirus/drug effects
20.
Sci Rep ; 11(1): 20864, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1479817

ABSTRACT

Following SARS-CoV-2 infection, some COVID-19 patients experience severe host driven adverse events. To treat these complications, their underlying etiology and drug treatments must be identified. Thus, a novel AI methodology MOATAI-VIR, which predicts disease-protein-pathway relationships and repurposed FDA-approved drugs to treat COVID-19's clinical manifestations was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. To assess each manifestation's molecular basis, their prioritized shared proteins were subject to global pathway analysis. Next, the molecular features associated with hallmark COVID-19 phenotypes, e.g. unusual neurological symptoms, cytokine storms, and blood clots were explored. In practice, 24/26 of the major clinical manifestations are successfully predicted. Three major uncharacterized manifestation categories including neoplasms are also found. The prevalence of neoplasms suggests that SARS-CoV-2 might be an oncovirus due to shared molecular mechanisms between oncogenesis and viral replication. Then, repurposed FDA-approved drugs that might treat COVID-19's clinical manifestations are predicted by virtual ligand screening of the most frequent comorbid protein targets. These drugs might help treat both COVID-19's severe adverse events and lesser ones such as loss of taste/smell.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , COVID-19/drug therapy , Computational Biology/methods , Neoplasms/complications , Nervous System Diseases/complications , Thrombosis/complications , Virus Replication , Benchmarking , Comorbidity , Computer Simulation , Cytokine Release Syndrome , Drug Discovery , Humans , Machine Learning , Molecular Medicine , Phenotype , SARS-CoV-2 , Treatment Outcome
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