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1.
Nihon Yakurigaku Zasshi ; 157(1): 27-30, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1609121

ABSTRACT

The new coronavirus (SARS-CoV-2) spread throughout the world and caused a pandemic with COVID-19, an infection caused by SARS-CoV-2. Even today, an increase in the number of cases has also been observed in Japan. Since the drugs used in drug repositioning have already been tested for safety and pharmacokinetics in humans, it is possible to skip some development tests, and since the manufacturing method of the drug has already been established, it is possible to shorten the development period and reduce R&D costs. Therefore, the drug repositioning method is one of the methods that should be tried in order to achieve the initial control of a pandemic. In Japan, it has been announced that research and development using drug repositioning has been conducted to date. The following are some of the candidates that have already been identified as COVID-19 therapeutic agents in Japan and are expected to be identified in the future.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , Pandemics , SARS-CoV-2
2.
Nihon Yakurigaku Zasshi ; 157(1): 41-46, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1609120

ABSTRACT

Although months have passed since WHO declared COVID-19 a global pandemic, only a limited number of clinically effective drugs are available, and the development of drugs to treat COVID-19 has become an urgent issue worldwide. The pace of new research on COVID-19 is extremely high and it is impossible to read every report. In order to tackle these problems, we leveraged our artificial intelligence (AI) system, Concept Encoder, to accelerate the process of drug repositioning. Concept Encoder is a patented AI system based on natural language processing technology and by deeply learning papers on COVID-19, the system identified a large group of genes implicated in COVID-19 pathogenesis. The AI system then generated a molecular linkage map for COVID-19, connecting the genes by learning the molecular relationship comprehensively. By thoroughly reviewing the resulting map and list of the genes with rankings, we found potential key players for disease progression and existing drugs that might improve COVID-19 survival. Here, we focus on potential targets and discuss the perspective of our approach.


Subject(s)
COVID-19 , Drug Repositioning , Artificial Intelligence , Humans , Pandemics , SARS-CoV-2
3.
Med Sci Monit ; 28: e935952, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1596813

ABSTRACT

On 4th November 2021, the first oral antiviral drug for COVID-19, molnupiravir (Lagevrio®), received full regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. Molnupiravir is an orally bioavailable antiviral drug for use at home when a SARS-CoV-2 test is positive. On 22nd December 2022, the FDA granted emergency use authorization (EUA) for the oral antiviral drug, nirmatrelvir/ritonavir (Paxlovid®) for adults and children with mild and moderate COVID-19 at increased risk of progression to severe COVID-19. These regulatory drug approvals come at a crucial time when new variants of concern of the SARS-CoV-2 virus are spreading rapidly. Although the FDA approved remdesivir (Veklury®) on 22nd October 2020 for use in adults and children for the treatment of COVID-19 requiring hospitalization, its use has been limited by the requirement for intravenous administration in a healthcare facility. The four FDA-approved therapeutic neutralizing monoclonal antibodies, imdevimab, bamlanivimab, etesevimab, and casirivimab are costly and also require medically-supervised intravenous administration. The availability of effective, low-cost oral antiviral drugs available in a community setting that can be used at an early stage of SARS-CoV-2 infection is now a priority in controlling COVID-19. An increasing number of repurposed antiviral drugs are currently under investigation or in the early stages of regulatory approval. This Editorial aims to present an update on the current status of orally bioavailable antiviral drug treatments for SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Administration, Oral , Antibodies, Monoclonal/therapeutic use , Cytidine/therapeutic use , Drug Approval , Drug Repositioning/trends , Humans , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , United States , United States Food and Drug Administration
4.
Nat Commun ; 12(1): 7327, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1585856

ABSTRACT

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Indoles/chemistry , Software , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , Indoles/therapeutic use , SARS-CoV-2/drug effects
5.
Int J Mol Sci ; 22(24)2021 Dec 18.
Article in English | MEDLINE | ID: covidwho-1580690

ABSTRACT

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify drug candidates that are able to block the entrance of the virus into human cells. By combining virtual screening with in vitro pseudovirus assays and antiviral assays in Human Lung Tissue (HLT) cells, we identify entrectinib as a potential antiviral drug.


Subject(s)
Benzamides/pharmacology , COVID-19/drug therapy , Indazoles/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacology , Benzamides/metabolism , COVID-19/metabolism , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning/methods , Humans , Indazoles/metabolism , Lung/pathology , Lung/virology , Molecular Docking Simulation , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vero Cells , Virus Attachment/drug effects
6.
Molecules ; 26(24)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572566

ABSTRACT

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP-3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Drug Repositioning/methods , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Acetates/chemistry , Acetates/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytidine Diphosphate Choline/chemistry , Cytidine Diphosphate Choline/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Uridine/analogs & derivatives , Uridine/chemistry , Uridine/pharmacology
7.
Future Microbiol ; 16: 1341-1370, 2021 11.
Article in English | MEDLINE | ID: covidwho-1555047

ABSTRACT

Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Middle East Respiratory Syndrome Coronavirus/drug effects , SARS-CoV-2/drug effects , Animals , COVID-19/virology , Cell Line , Chlorocebus aethiops , Drug Repositioning/methods , Humans , Molecular Docking Simulation , Pandemics/prevention & control , Vero Cells
8.
Biomolecules ; 11(12)2021 12 04.
Article in English | MEDLINE | ID: covidwho-1554985

ABSTRACT

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Caspase Inhibitors/pharmacology , Drug Repositioning/methods , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , COVID-19/drug therapy , Caspase 1/metabolism , Caspase Inhibitors/chemistry , Humans , Inflammation/drug therapy , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
9.
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
10.
Biosci Trends ; 15(5): 345-349, 2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1528987

ABSTRACT

Coronavirus disease 19 (COVID-19) continues to rage as a global pandemic. A number of potential therapeutic agents have been explored over the past year or two. However, numerous drugs that were expected to prove highly effective, such as lopinavir/ritonavir and remdesivir, have been found to have little benefit in large clinical trials. Interleukin-6 receptor antagonists, glucocorticoids, Janus kinase inhibitors, and some antivirals have been found to provide significant benefits in terms of reducing viral load, reducing the time of nucleic acid conversion, or improving survival. For example, bamlanivimab and etesevimab, which are newly designed monoclonal antibodies against the surface spike protein S1 subunit receptor-binding domain (RBD) of SARS-CoV-2, have a significant effect on reducing the viral load and the hospitalization rate of patients with mild COVID-19. Several vaccines against SARS-CoV-2 have been widely administered worldwide and have provided good protection. Nevertheless, the increasingly hardy variants of the virus have raised the requirements for vaccine design. Perhaps RBD-based vaccines are a viable way to defend against variants, but this still needs to be verified in a large sample. Therefore, this paper provides an update on the treatment options for COVID-19 based on three previously proposed dimensions of drug screening: standard assays of existing broad-spectrum antivirals, screening of chemical libraries, and redevelopment of new, specific drugs.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Animals , Antibodies, Monoclonal/therapeutic use , COVID-19 Vaccines , Humans , Randomized Controlled Trials as Topic
11.
mBio ; 12(2)2021 03 30.
Article in English | MEDLINE | ID: covidwho-1522913

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 µM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Replication/drug effects , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , Evans Blue/pharmacology , Humans , Molecular Docking Simulation , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sulfones/pharmacology , Surface Plasmon Resonance , Vero Cells
12.
J Biomol Struct Dyn ; 39(13): 4633-4646, 2021 08.
Article in English | MEDLINE | ID: covidwho-1521980

ABSTRACT

Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been performed by a virtual drug repurposing approach. First, drug shape-based screening (among FDA approved drugs) with a known template of MTase inhibitor, sinefungin was done and best compounds with high similarity scores were selected. In addition to the selected compounds, 4 nucleoside analogs of anti-viral (Raltgravir, Maraviroc and Favipiravir) and anti-inflammatory (Prednisolone) drugs were selected for further investigations. Then, binding energies and interaction modes were found by molecular docking approaches and compouds with lower energy were selected for further investigation. After that, Molecular dynamics (MD) simulation was carried to test the potential selected compounds in a realistic environment. The results showed that Raltegravir and Maraviroc among other compounds can bind strongly to the active site of the protein compared to sinefungin, and can be potential candidates to inhibit NSP-16. Also, the MD simulation results suggested that the Maraviroc and Raltegravir are more effective drug candidates than Sinefungin for inhibiting the enzyme. It is concluded that Raltegravir and Maraviroc which may be used in the treatment of COVID-19 after Invitro and invivo studies and clinical trial for final confirmation of drug effectiveness. Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Drug Repositioning , Antiviral Agents/pharmacology , Humans , Molecular Docking Simulation , SARS-CoV-2
13.
J Biomol Struct Dyn ; 39(13): 4659-4670, 2021 08.
Article in English | MEDLINE | ID: covidwho-1521979

ABSTRACT

The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Drug Repositioning , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , SARS-CoV-2
14.
Sci Rep ; 11(1): 21872, 2021 11 08.
Article in English | MEDLINE | ID: covidwho-1506466

ABSTRACT

Severe acute respiratory syndrome (SARS) is a highly contagious viral respiratory illness. This illness is spurred on by a coronavirus known as SARS-associated coronavirus (SARS-CoV). SARS was first detected in Asia in late February 2003. The genome of this virus is very similar to the SARS-CoV-2. Therefore, the study of SARS-CoV disease and the identification of effective drugs to treat this disease can be new clues for the treatment of SARS-Cov-2. This study aimed to discover novel potential drugs for SARS-CoV disease in order to treating SARS-Cov-2 disease based on a novel systems biology approach. To this end, gene co-expression network analysis was applied. First, the gene co-expression network was reconstructed for 1441 genes, and then two gene modules were discovered as significant modules. Next, a list of miRNAs and transcription factors that target gene co-expression modules' genes were gathered from the valid databases, and two sub-networks formed of transcription factors and miRNAs were established. Afterward, the list of the drugs targeting obtained sub-networks' genes was retrieved from the DGIDb database, and two drug-gene and drug-TF interaction networks were reconstructed. Finally, after conducting different network analyses, we proposed five drugs, including FLUOROURACIL, CISPLATIN, SIROLIMUS, CYCLOPHOSPHAMIDE, and METHYLDOPA, as candidate drugs for SARS-CoV-2 coronavirus treatment. Moreover, ten miRNAs including miR-193b, miR-192, miR-215, miR-34a, miR-16, miR-16, miR-92a, miR-30a, miR-7, and miR-26b were found to be significant miRNAs in treating SARS-CoV-2 coronavirus.


Subject(s)
COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Drug Repositioning , Gene Expression Profiling , Gene Expression Regulation, Viral , SARS-CoV-2 , Computational Biology , Gene Regulatory Networks , Genes, Viral , Genetic Techniques , Humans , MicroRNAs/metabolism , Oligonucleotide Array Sequence Analysis , Systems Biology , Transcription Factors
16.
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
18.
ACS Infect Dis ; 7(6): 1303-1316, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1493009

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has disrupted global healthcare and economic systems throughout 2020 with no clear end in sight. While the pandemic continues to have deleterious effects across the globe, mechanisms for disrupting disease transmission have relied on behavioral controls (e.g., social distancing, masks, and hygiene) as there are currently no vaccines approved for use and limited therapeutic options. As this pandemic has demonstrated our vulnerability to newly emerging viruses, there has been strong interest in utilizing proteomics approaches to identify targets for repurposed drugs as novel therapeutic candidates that could be fast-tracked for human use. Building on a previous discussion on the combination of proteomics technologies with clinical data for combating emerging viruses, we discuss how these technologies are being employed for COVID-19 and the current state of knowledge regarding repurposed drugs in these efforts.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Drug Repositioning , Humans , Pandemics , Proteomics , SARS-CoV-2
19.
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
20.
Mol Syst Biol ; 17(11): e10260, 2021 11.
Article in English | MEDLINE | ID: covidwho-1488874

ABSTRACT

Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM), revealing complicated host metabolism reprogramming during SARS-CoV-2 infection. We next applied the GEM-based metabolic transformation algorithm to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco-2 cells. Further generating and analyzing RNA-sequencing data of remdesivir-treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti-SARS-CoV-2 drug. Our study provides clinical data-supported candidate anti-SARS-CoV-2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/metabolism , Metabolic Networks and Pathways/genetics , Pandemics , SARS-CoV-2/physiology , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Animals , COVID-19/drug therapy , COVID-19/virology , Caco-2 Cells , Chlorocebus aethiops , Datasets as Topic , Drug Development , Drug Repositioning , Host-Pathogen Interactions , Humans , RNA, Small Interfering , Sequence Analysis, RNA , Vero Cells
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