Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 106
Filter
1.
International Journal of Molecular Sciences ; 23(7):3649-N.PAG, 2022.
Article in English | Academic Search Complete | ID: covidwho-1834806

ABSTRACT

The coronavirus disease 2019 (COVID-19) epidemic is currently raging around the world at a rapid speed. Among COVID-19 patients, SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) is the main contribution to the high ratio of morbidity and mortality. However, clinical manifestations between SARS-CoV-2-associated ARDS and non-SARS-CoV-2-associated ARDS are quite common, and their therapeutic treatments are limited because the intricated pathophysiology having been not fully understood. In this study, to investigate the pathogenic mechanism of SARS-CoV-2-associated ARDS and non-SARS-CoV-2-associated ARDS, first, we constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via database mining. With the help of host-pathogen RNA sequencing (RNA-Seq) data, real HPI-GWGEN of COVID-19-associated ARDS and non-viral ARDS were obtained by system modeling, system identification, and Akaike information criterion (AIC) model order selection method to delete the false positives in candidate HPI-GWGEN. For the convenience of mitigation, the principal network projection (PNP) approach is utilized to extract core HPI-GWGEN, and then the corresponding core signaling pathways of COVID-19-associated ARDS and non-viral ARDS are annotated via their core HPI-GWGEN by KEGG pathways. In order to design multiple-molecule drugs of COVID-19-associated ARDS and non-viral ARDS, we identified essential biomarkers as drug targets of pathogenesis by comparing the core signal pathways between COVID-19-associated ARDS and non-viral ARDS. The deep neural network of the drug–target interaction (DNN-DTI) model could be trained by drug–target interaction databases in advance to predict candidate drugs for the identified biomarkers. We further narrowed down these predicted drug candidates to repurpose potential multiple-molecule drugs by the filters of drug design specifications, including regulation ability, sensitivity, excretion, toxicity, and drug-likeness. Taken together, we not only enlighten the etiologic mechanisms under COVID-19-associated ARDS and non-viral ARDS but also provide novel therapeutic options for COVID-19-associated ARDS and non-viral ARDS. [ FROM AUTHOR] Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

2.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-335156

ABSTRACT

Sublineages of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron variants continue to amass mutations in the spike (S) glycoprotein, which leads to immune evasion and rapid spread of the virus across the human population. Here we demonstrate the susceptibility of the Omicron variant BA.1 (B.1.1.529.1) to four repurposable drugs, Methylene blue (MB), Mycophenolic acid (MPA), Posaconazole (POS), and Niclosamide (Niclo) in post-exposure treatments of primary human airway cell cultures. MB, MPA, POS, and Niclo are known to block infection of human nasal and bronchial airway epithelial explant cultures (HAEEC) with the Wuhan strain, and four variants of concern (VoC), Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28), Delta (B.1.617.2) (1, 2). Our results not only show broad anti-coronavirus effects of MB, MPA, POS and Niclo, but also demonstrate that the Omicron variant BA.1 (B.1.1.529.1) sheds infectious virus from HAEEC over at least 15 days, and maintains both intracellular and extracellular viral genomic RNA without overt toxicity, suggesting viral persistence. The data underscore the broad effects of MB, MPA, POS, and Niclo against SARS-CoV-2 and the currently circulating VoC, and reinforce the concept of repurposing drugs in clinical trials against COVID-19.

3.
International Journal of Current Pharmaceutical Research ; 14(2):11-14, 2022.
Article in English | EMBASE | ID: covidwho-1822679

ABSTRACT

Covid 19, the disease first identified in the Chine city of Wuhan in December 2019 had been declared as a pandemic by WHO. This pandemic caused by Sars Cov 2 has resulted in 165.5 million infections and 3.5 million deaths globally, as of now. Till now no drug isavailable to fight against this deadly disease. The strategy adopted by drug discovery groups is drug repurposing which has not met much success with chloroquine as well as remdesivir. A relatively new candidate in the fray is favipravir which was originally developed by Toyama chemical company against influenza strains. Few synthetic routes are developed for this compound and the safety concerns are relatively few. If favourable results from the ongoing clinicaltrials arise, that may provide the therapeutic community a lethalweapon against the virus.

4.
Pharmaceuticals ; 15(4), 2022.
Article in English | EMBASE | ID: covidwho-1822433

ABSTRACT

SARS-CoV-2 is the etiological agent COVID-19, one of the most impactful health crises afflicting humanity in recent decades. While research advances have yielded several treatment and prevention options, the pandemic is slow to abate, necessitating an expansion of our treatment arsenal. As a member of the coronaviridae, SARS-CoV-2 contains several ion channels, of which E and 3a are the best characterized. Since ion channels as a family are excellent drug targets, we sought to inhibit both viroporins as a means to curb infectivity. In a previous targeted study, we identified several blockers to each channel from an extensive drug repurposing library. Herein, we examined the ability of said compounds on the whole virus in cellulo. Gratifyingly, many of the blockers exhibited antiviral activity in a stringent assay examining protection from viral-driven death. In particular, darapladib and flumatinib, both 3a blockers, displayed potent antiviral activity. Furthermore, appreciable synergism between flumatinib and several E blockers was identified in a concentration regime in which the compounds are present in human plasma following oral administration. Taken together, targeting ion channels represents a promising approach to both augment and complement our antiviral arsenal against COVID-19.

5.
International Clinical Psychopharmacology ; 37(3):77-78, 2022.
Article in English | EMBASE | ID: covidwho-1816378
6.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-334098

ABSTRACT

Background: Despite a great deal of interest in the application of artificial intelligence (AI) to sepsis/critical illness, most current approaches are limited in their potential impact: prediction models do not (and cannot) address the lack of effective therapeutics and current approaches to enhancing the treatment of sepsis focus on optimizing the application of existing interventions, and thus cannot address the development of new treatment options/modalities. The inability to test new therapeutic applications was highlighted by the generally unsatisfactory results from drug repurposing efforts in COVID-19. Hypothesis: Addressing this challenge requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training the game-playing AIs. We have previously demonstrated the potential of this method in the context of bacterial sepsis in which the microbial infection is responsive to antibiotic therapy. The current work addresses the control problem of multi-modal, adaptive immunomodulation in the circumstance where there is no effective anti-pathogen therapy (e.g., in a novel viral pandemic or in the face of resistant microbes). Methods: This is a proof-of-concept study that determines the controllability of sepsis without the ability to pharmacologically suppress the pathogen. We use as a surrogate system a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. The DRL algorithm ‘trains’ an AI on simulations of infection where both the control and observation spaces are limited to operating upon the defined immune mediators included in the IIRABM (a total of 11). Policies were learned using the Deep Deterministic Policy Gradient approach, with the objective function being a return to baseline system health. Results: DRL trained an AI policy that improved system mortality from 85% to 10.4%. Control actions affected every one of the 11 targetable cytokines and could be divided into those with static/unchanging controls and those with variable/adaptive controls. Adaptive controls primarily targeted 3 different aspects of the immune response: 2nd order pro-inflammation governing TH1/TH2 balance, primary anti-inflammation, and inflammatory cell proliferation. Discussion: The current treatment of sepsis is hampered by limitations in therapeutic options able to affect the biology of sepsis. This is heightened in circumstances where no effective antimicrobials exist, as was the case for COVID-19. Current AI methods are intrinsically unable to address this problem;doing so requires training AIs in contexts that fully represent the counterfactual space of potential treatments. The synthetic data needed for this task is only possible through the use of high-resolution, mechanism-based simulations. Finally, being able to treat sepsis will require a reorientation as to the sensing and actuating requirements needed to develop these simulations and bring them to the bedside.

7.
J Comput Biol ; 2022 Apr 07.
Article in English | MEDLINE | ID: covidwho-1795401

ABSTRACT

This study formulates antiviral repositioning as a matrix completion problem wherein the antiviral drugs are along the rows and the viruses are along the columns. The input matrix is partially filled, with ones in positions where the antiviral drug has been known to be effective against a virus. The curated metadata for antivirals (chemical structure and pathways) and viruses (genomic structure and symptoms) are encoded into our matrix completion framework as graph Laplacian regularization. We then frame the resulting multiple graph regularized matrix completion (GRMC) problem as deep matrix factorization. This is solved by using a novel optimization method called HyPALM (Hybrid Proximal Alternating Linearized Minimization). Results of our curated RNA drug-virus association data set show that the proposed approach excels over state-of-the-art GRMC techniques. When applied to in silico prediction of antivirals for COVID-19, our approach returns antivirals that are either used for treating patients or are under trials for the same.

8.
Curr Neuropharmacol ; 20(4): 777-781, 2022.
Article in English | MEDLINE | ID: covidwho-1785246

ABSTRACT

BACKGROUND: As the World faces unprecedented pandemic caused by SARS-CoV-2 virus, repositioning of existing drugs to treatment of COVID-19 disease is urgently awaited, provided that high quality scientific evidence supporting safety and efficacy in this new indication is gathered. Efforts concerning drugs repositioning to COVID-19 were mostly focused on antiviral drugs, or drugs targeting the late phase of the disease. METHODS: Based on published research, the pharmacological activities of fluvoxamine and amantadine, two well-known drugs widely used in clinical practice for psychiatric and neurological diseases, respectively, have been reviewed, with a focus on their potential therapeutic importance in the treatment of COVID-19. RESULTS: Several preclinical and clinical reports were identified suggesting that these two drugs might exert protective effects in the early phases of COVID-19. CONCLUSION: Preclinical and early clinical evidence are presented indicating that these drugs hold promise to prevent COVID-19 progression when administered early during the course of infection.


Subject(s)
COVID-19 , Fluvoxamine , Amantadine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Central Nervous System , Central Nervous System Agents , Fluvoxamine/therapeutic use , Humans , SARS-CoV-2
9.
Eur J Med Chem ; 234: 114239, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1783304

ABSTRACT

Compared with traditional de novo drug discovery, drug repurposing has become an attractive drug discovery strategy due to its low-cost and high efficiency. Through a comprehensive analysis of the candidates that have been identified with drug repositioning potentials, it is found that although some drugs do not show obvious advantages in the original indications, they may exert more obvious effects in other diseases. In addition, some drugs have a synergistic effect to exert better clinical efficacy if used in combination. Particularly, it has been confirmed that drug repositioning has benefits and values on the current public health emergency such as the COVID-19 pandemic, which proved the great potential of drug repositioning. In this review, we systematically reviewed a series of representative drugs that have been repositioned for different diseases and illustrated successful cases in each disease. Especially, the mechanism of action for the representative drugs in new indications were explicitly explored for each disease, we hope this review can provide important insights for follow-up research.


Subject(s)
COVID-19 , Drug Repositioning , COVID-19/drug therapy , Drug Discovery , Humans , Pandemics
10.
Int J Mol Sci ; 23(7)2022 Apr 03.
Article in English | MEDLINE | ID: covidwho-1776250

ABSTRACT

The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of Mpro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 Mpro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 Mpro.


Subject(s)
COVID-19 , Drug Repositioning , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
11.
Future Virol ; 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1770942

ABSTRACT

Novel COVID-19 is a public health emergency that poses a serious threat to people worldwide. Given the virus spreading so quickly, novel antiviral medications are desperately needed. Repurposing existing drugs is the first strategy. Anti-parasitic drugs were among the first to be considered as a potential treatment option for this disease. Even though many papers have discussed the efficacy of various anti-parasitic drugs in treating COVID-19 separately, so far, no single study comprehensively discussed these drugs. This study reviews some anti-parasitic recommended drugs to treat COVID-19, in terms of function and in vitro as well as clinical results. Finally, we briefly review the advanced techniques, such as artificial intelligence, that have been used to find effective drugs for the treatment of COVID-19.

12.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-331135

ABSTRACT

Background: Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Methods: Inhibition of angiotensin-converting enzyme 2 (ACE2) caused by the spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We performed drug repositioning analysis to identify drug candidates that reverse gene expression pattern in L1000 lung cell line HCC515 treated with ACE2 inhibitor. We confirmed these drug candidates by similar bioinformatics analysis using lung tissues from patients deceased from COVID-19. We further investigated deregulated genes and pathways related to lung injury, as well as the gene-pathway-drug candidate relationships. Results: We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19. Further bioinformatics analysis shows that 12 significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues. These include signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and chemokine signaling pathways. All 12 pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares 11 of 12 pathways with COL-3 and common target genes such as RHOA. It also uniquely targets other genes related to lung injury, such as CALR and MMP14. Conclusions: This study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have potential as repurposed drugs for its treatment.

13.
IEEE High Performance Extreme Computing Conference (HPEC) ; 2021.
Article in English | Web of Science | ID: covidwho-1764820

ABSTRACT

Drug repositioning (also called "drug repurposing") is a drug development strategy that saves time and money by finding new uses for existing drugs. While a variety of computational approaches to drug repositioning exist, recent work has shown that tensor decomposition, an unsupervised learning technique for finding latent structure in multidimensional data, is a useful tool for drug repositioning. The known relationships between drugs, targets, and diseases can easily be encoded as a tensor, and by learning a low-rank representation of this tensor, decompositions can complete missing entries and therefore predict novel drug-disease associations. Multiple recent works, in the context of cancer and COVID-19 drug discovery, have used joint tensor decompositions to suggest drug repositioning candidates. While these methods make high-quality predictions, they rely on specialized decompositions formulated for specific problems. In this work, we use ENSIGN, a suite of tensor decomposition tools, to show that CP tensor decompositions of a single tensor encoding drug-target-disease associations are capable of predicting verifiable drug repositioning candidates. Because the tensors generated by drug repositioning problems are sparse, we introduce a filtered tensor construction to limit the span of the tensor without losing information needed to learn the relevant associations. We show that our method predicts verifiable novel drug-disease associations in cancer and COVID-19 data. The simplicity of our approach makes it an attractive tool for biomedical researchers looking for out-of-the-box solutions, and ENSIGN brings an added level of usability and scalability.

14.
Journal of the Association of Physicians of India ; 69(June):85-85, 2021.
Article in English | GIM | ID: covidwho-1755998

ABSTRACT

This paper reports two cases of AKI with favipiravir induced nephrotoxicity. Patient 1: 38-year male, confirmed reverse transcriptase polymerase chain reaction positive (RT-PCR) positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) and moderate pneumonia was given hydroxy-chloroquinine (HCQ) 400 mg BID followed by 200 mg BID for 10 days and favipiravir at 1600 mg BID followed by 600 mg BID for 5 days. Patient 2: 51-year male RT-PCR positive, severe COVID-19 was started on HCQ and favipiravir at same dose as in patient one along with methylprednisolone 40 mg BID for days and enoxaparin 40 mg subcutaneous once daily. In conclusion, the authors believe as many repurposed drugs are being used for COVID-19 on experimental and compassionate basis without well conducted research, the clinicians need to be very careful of any new adverse event. The AKI like in any other patient needs comprehensive review for all possible etiology before linking it to COVID-19.

15.
Journal of the Association of Physicians of India ; 69(June):11-12, 2021.
Article in English | GIM | ID: covidwho-1755946

ABSTRACT

Preventive strategies are needed to be considered more due to the rising tide of COVID-19 cases. A number of preventive strategies have been advocated by international agencies such as the World Health Organization (WHO), Centre for Disease Control (CDC) and implemented by governments across the world. These include various protective measures such as the use of masks, Personal Protective Equipment (PPE) kits, hand washing, test and contact tracing, selfisolation, home quarantine, admission and many other measures. One of the most pragmatic strategies would be to re-examine what drugs are available in the market that may have a prophylactic role against COVID-19. A great many of the drugs considered were antivirals, including Anti-HIV drugs, ivermectin9 anti-rheumatic drugs, such as hydroxychloroquine (HCQ). In conclusion, it would therefore be important for policymakers to take note of these findings and from other relevant studies done in India regarding repurposing such drugs.

16.
ACS Infectious Diseases ; 7(6):1297-1554, 2021.
Article in English | GIM | ID: covidwho-1755434

ABSTRACT

This special issue showcases diverse contributions and progress made in the area of Antiviral Therapeutics. It showcases work on the discovery, development, and optimization of both direct-acting and host-targeted antivirals combating both known and newly emerging viral pathogens. The issue also features groundbreaking work in the development of new strategies for antiviral target discovery and antiviral interventions that leverage discoveries in virus biology and new computational and experimental approaches. Given the prominence of drug-repurposing and de novo discovery efforts during the SARS-CoV-2 pandemic, it also presents highlighting both the progress and potential challenges of these approaches. These works, submitted by colleagues across the globe working in academia, industry, and government, form a special issue highlighting what a community of researchers interested in viral therapeutic discovery, can accomplish and the challenges that remain.

17.
Med Drug Discov ; 14: 100120, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1747692

ABSTRACT

While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such 'pan-pathogen' antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome which are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19.

18.
Open Forum Infectious Diseases ; 8(SUPPL 1):S354, 2021.
Article in English | EMBASE | ID: covidwho-1746494

ABSTRACT

Background. The outbreak of COVID-19 pandemic in China regarded as a major health/economic hazard. The importance of coming up with mechanisms for preventing or treating COVID-19 has been felt across the world. This work aimed at examining the efficiency of Sitagliptin (SIT) and human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) against SARS-CoV-2. Methods. SIT-TAT nano-conjugates were prepared according to a full three-factor bi-level (23) factorial design. SIT concentration (mM, X1), TAT concentration (mM, X2), and pH (X3) were selected as the factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) and Transmission electron microscope was carried out. In addition, IC50 in Vero E6 cells, In vitro 3CL-protease inhibition and docking tests were investigated. Results. The prepared complex's formula was as follows 1: 1 SIT: TAT molar ratio, whereas zeta potential and particle size values were at 34.17 mV and 97.19 nm, respectively. This combination did exhibit its antiviral potentiality against SARS-CoV-2 via IC50 values of 9.083 5.415, and 16.14 μM for TAT, SIT-TAT, and SIT, respectively. In addition, the complex SIT-TAT showed a significant (P < 0.001) viral-3CL-protease inhibitory effect (IC50 = 3.959 μM ± 0.011) in comparison to isolated components (IC50 = 10.93 μM ± 0.25) and TAT (IC50 = 8.128 μM ± 0.42). This was further confirmed via in silico study. Molecular docking investigation has shown promising binding affinity of the formula components towards SARS-CoV-2 main protease (3-CL). Conclusion. While offering significant binding interactions with protein's key pocket residues, an optimized formulation of SIT-TAT could guarantee both the enhanced delivery to the target cells and the improved cellular uptake. The presented findings would guarantee further investigations regarding formula optimization against SARS-CoV-2.

19.
Brief Bioinform ; 2022 Mar 03.
Article in English | MEDLINE | ID: covidwho-1740806

ABSTRACT

Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant variants and favorable balance of costs and risks. Genomic methods have produced a large number of robust host factors, providing candidates for identification of antiviral drug targets. However, there is a lack of global perspectives and systematic prioritization of known virus-targeted host proteins (VTHPs) and drug targets. There is also a need for host-directed repositioned antivirals. Here, we integrated 6140 VTHPs and grouped viral infection modes from a new perspective of enriched pathways of VTHPs. Clarifying the superiority of nonessential membrane and hub VTHPs as potential ideal targets for repositioned antivirals, we proposed 543 candidate VTHPs. We then presented a large-scale drug-virus network (DVN) based on matching these VTHPs and drug targets. We predicted possible indications for 703 approved drugs against 35 viruses and explored their potential as broad-spectrum antivirals. In vitro and in vivo tests validated the efficacy of bosutinib, maraviroc and dextromethorphan against human herpesvirus 1 (HHV-1), hepatitis B virus (HBV) and influenza A virus (IAV). Their drug synergy with clinically used antivirals was evaluated and confirmed. The results proved that low-dose dextromethorphan is better than high-dose in both single and combined treatments. This study provides a comprehensive landscape and optimization strategy for druggable VTHPs, constructing an innovative and potent pipeline to discover novel antiviral host proteins and repositioned drugs, which may facilitate their delivery to clinical application in translational medicine to combat fatal and spreading viral infections.

20.
Methods ; 198: 3-10, 2022 02.
Article in English | MEDLINE | ID: covidwho-1721113

ABSTRACT

The coronavirus disease 2019 (COVID-19) has outbreak since early December 2019, and COVID-19 has caused over 100 million cases and 2 million deaths around the world. After one year of the COVID-19 outbreak, there is no certain and approve medicine against it. Drug repositioning has become one line of scientific research that is being pursued to develop an effective drug. However, due to the lack of COVID-19 data, there is still no specific drug repositioning targeting the COVID-19. In this paper, we propose a framework for COVID-19 drug repositioning. This framework has several advantages that can be exploited: one is that a local graph aggregating representation is used across a heterogeneous network to address the data sparsity problem; another is the multi-hop neighbors of the heterogeneous graph are aggregated to recall as many COVID-19 potential drugs as possible. Our experimental results show that our COVDR framework performs significantly better than baseline methods, and the docking simulation verifies that our three potential drugs have the ability to against COVID-19 disease.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Antiviral Agents , Drug Repositioning , Humans , Molecular Docking Simulation , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL