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1.
Commun Biol ; 5(1): 212, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1735294

ABSTRACT

Internalization of membrane proteins plays a key role in many physiological functions; however, highly sensitive and versatile technologies are lacking to study such processes in real-time living systems. Here we describe an assay based on bioluminescence able to quantify membrane receptor trafficking for a wide variety of internalization mechanisms such as GPCR internalization/recycling, antibody-mediated internalization, and SARS-CoV2 viral infection. This study represents an alternative drug discovery tool to accelerate the drug development for a wide range of physiological processes, such as cancer, neurological, cardiopulmonary, metabolic, and infectious diseases including COVID-19.


Subject(s)
Drug Discovery/methods , Membrane Proteins , Protein Transport/physiology , Spectrometry, Fluorescence/methods , COVID-19 , Drug Development/methods , HEK293 Cells , Humans , Luciferases/genetics , Luciferases/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Microscopy, Fluorescence , Nanotechnology , Receptors, G-Protein-Coupled , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Virus Internalization
2.
Pharm Biol ; 60(1): 509-524, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1713414

ABSTRACT

CONTEXT: Since the outbreak of SARS-CoV-2, researchers have been working on finding ways to prevent viral entry and pathogenesis. Drug development from naturally-sourced pharmacological constituents may be a fruitful approach to COVID-19 therapy. OBJECTIVE: Most of the published literature has focussed on medicinal plants, while less attention has been given to biodiverse sources such as animal, marine, and microbial products. This review focuses on highlighting natural products and their derivatives that have been evaluated for antiviral, anti-inflammatory, and immunomodulatory properties. METHODS: We searched electronic databases such as PubMed, Scopus, Science Direct and Springer Link to gather raw data from publications up to March 2021, using terms such as 'natural products', marine, micro-organism, and animal, COVID-19. We extracted a number of documented clinical trials of products that were tested in silico, in vitro, and in vivo which paid specific attention to chemical profiles and mechanisms of action. RESULTS: Various classes of flavonoids, 2 polyphenols, peptides and tannins were found, which exhibit inhibitory properties against viral and host proteins, including 3CLpro, PLpro, S, hACE2, and NF-κB, many of which are in different phases of clinical trials. DISCUSSION AND CONCLUSIONS: The synergistic effects of logical combinations with different mechanisms of action emphasizes their value in COVID19 management, such as iota carrageenan nasal spray, ermectin oral drops, omega-3 supplementation, and a quadruple treatment of zinc, quercetin, bromelain, and vitamin C. Though in vivo efficacy of these compounds has yet to be established, these bioproducts are potentially useful in counteracting the effects of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/drug therapy , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/administration & dosage , Antiviral Agents/isolation & purification , Biological Products/isolation & purification , COVID-19/virology , Drug Development/methods , Drug Synergism , Humans , /isolation & purification , /pharmacology
4.
Molecules ; 27(2)2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1625662

ABSTRACT

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences of nucleotides are designed to precisely target other oligonucleotides, usually RNA species, and are modified to protect them from degradation by nucleases. Their specificity is due to their sequence, so it is possible to target any RNA sequence that is already known. These molecules are very versatile and adaptable given that their sequence and chemistry can be custom manufactured. Based on the chemistry being used, their activity may significantly change and their effects on cell function and phenotypes can differ dramatically. While some will cause the target RNA to decay, others will only bind to the target and act as a steric blocker. Their incredible versatility is the key to manipulating several aspects of nucleic acid function as well as their process, and alter the transcriptome profile of a specific cell type or tissue. For example, they can be used to modify splicing or mask specific sites on a target. The entire design rather than just the sequence is essential to ensuring the specificity of the ASO to its target. Thus, it is vitally important to ensure that the complete process of drug design and testing is taken into account. ASOs' adaptability is a considerable advantage, and over the past decades has allowed multiple new drugs to be approved. This, in turn, has had a significant and positive impact on patient lives. Given current challenges presented by the COVID-19 pandemic, it is necessary to find new therapeutic strategies that would complement the vaccination efforts being used across the globe. ASOs may be a very powerful tool that can be used to target the virus RNA and provide a therapeutic paradigm. The proof of the efficacy of ASOs as an anti-viral agent is long-standing, yet no molecule currently has FDA approval. The emergence and widespread use of RNA vaccines during this health crisis might provide an ideal opportunity to develop the first anti-viral ASOs on the market. In this review, we describe the story of ASOs, the different characteristics of their chemistry, and how their characteristics translate into research and as a clinical tool.


Subject(s)
Drug Development/methods , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/pharmacology , Animals , COVID-19/therapy , Drug Approval , Drug Design , Humans , Oligonucleotides, Antisense/therapeutic use , SARS-CoV-2/drug effects , United States , United States Food and Drug Administration
6.
Sci Rep ; 11(1): 23315, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1550334

ABSTRACT

The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/metabolism , Drug Development/methods , Drug Repositioning/methods , Benzamides/pharmacology , COVID-19/drug therapy , Cell Line , Computer Simulation , Coronavirus/chemistry , Databases, Pharmaceutical , Drug Discovery/methods , Host-Pathogen Interactions , Humans , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Triazines/pharmacology
7.
Clin Pharmacol Ther ; 111(3): 572-578, 2022 03.
Article in English | MEDLINE | ID: covidwho-1527428

ABSTRACT

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID-19) pandemic. Model-informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID-19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 , Drug Development/methods , Models, Biological , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/pharmacology , COVID-19/drug therapy , COVID-19/epidemiology , Drug Approval , Drug Repositioning , Humans , Pharmacology, Clinical/methods , SARS-CoV-2/immunology
8.
Clin Transl Sci ; 14(6): 2348-2359, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526356

ABSTRACT

Coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral infection, which can lead to pneumonia, lung injury, and death in susceptible populations. Understanding viral dynamics of SARS-CoV-2 is critical for development of effective treatments. An Immune-Viral Dynamics Model (IVDM) is developed to describe SARS-CoV-2 viral dynamics and COVID-19 disease progression. A dataset of 60 individual patients with COVID-19 with clinical viral load (VL) and reported disease severity were assembled from literature. Viral infection and replication mechanisms of SARS-CoV-2, viral-induced cell death, and time-dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Disease severity are tested as a covariate to model parameters. The IVDM was fitted to the data and parameters were estimated using the nonlinear mixed-effect model. The model can adequately describe individual viral dynamics profiles, with disease severity identified as a covariate on infected cell death rate. The modeling suggested that it takes about 32.6 days to reach 50% of maximum cell-based immunity. Simulations based on virtual populations suggested a typical mild case reaches VL limit of detection (LOD) by 13 days with no treatment, a moderate case by 17 days, and a severe case by 41 days. Simulations were used to explore hypothetical treatments with different initiation time, disease severity, and drug effects to demonstrate the usefulness of such modeling in informing decisions. Overall, the IVDM modeling and simulation platform enables simulations for viral dynamics and treatment efficacy and can be used to aid in clinical pharmacokinetic/pharmacodynamic (PK/PD) and dose-efficacy response analysis for COVID-19 drug development.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Development/methods , Host Microbial Interactions/immunology , Models, Biological , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Cell Death/drug effects , Cell Death/immunology , Datasets as Topic , Dose-Response Relationship, Drug , Host Microbial Interactions/drug effects , Humans , Nonlinear Dynamics , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severity of Illness Index , Treatment Outcome , Viral Load
10.
Nat Rev Drug Discov ; 20(11): 817-838, 2021 11.
Article in English | MEDLINE | ID: covidwho-1371218

ABSTRACT

Over the past several decades, messenger RNA (mRNA) vaccines have progressed from a scepticism-inducing idea to clinical reality. In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts. Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis. In this Review, we describe the technologies that underlie mRNA vaccines, with an emphasis on lipid nanoparticles and other non-viral delivery vehicles. We also overview the pipeline of mRNA vaccines against various infectious disease pathogens and discuss key questions for the future application of this breakthrough vaccine platform.


Subject(s)
COVID-19/prevention & control , Communicable Disease Control , Vaccines, Synthetic , COVID-19/epidemiology , Clinical Trials as Topic , Communicable Disease Control/methods , Communicable Disease Control/trends , Drug Design , Drug Development/methods , Humans , RNA, Messenger/genetics , SARS-CoV-2 , Vaccines, Synthetic/classification , Vaccines, Synthetic/pharmacology
13.
Viruses ; 13(7)2021 06 22.
Article in English | MEDLINE | ID: covidwho-1403875

ABSTRACT

Mammarenaviruses are prevalent pathogens distributed worldwide, and several strains cause severe cases of human infections with high morbidity and significant mortality. Currently, there is no FDA-approved antiviral drugs and vaccines against mammarenavirus and the potential treatment option is limited to an off-label use of ribavirin that shows only partial protective effect and associates with side effects. For the past few decades, extensive research has reported potential anti-mammarenaviral drugs and their mechanisms of action in host as well as vaccine candidates. This review describes current knowledge about mammarenavirus virology, progress of antiviral drug development, and technical strategies of drug screening.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae/drug effects , Drug Development/methods , High-Throughput Screening Assays , A549 Cells , Animals , Arenaviridae/pathogenicity , Chlorocebus aethiops , Clinical Trials as Topic , Drug Repositioning , HEK293 Cells , Humans , Ribavirin/pharmacology , Vero Cells , Virus Replication/drug effects
14.
Nat Commun ; 12(1): 3201, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1387343

ABSTRACT

Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2.


Subject(s)
Coronavirus 3C Proteases/chemistry , Coronavirus Papain-Like Proteases/chemistry , Drug Development/methods , Drug Discovery/methods , High-Throughput Screening Assays/methods , Histone-Lysine N-Methyltransferase/chemistry , Animals , Cell Survival , Chlorocebus aethiops , Computational Chemistry , Crystallography, X-Ray , Databases, Protein , Drug Design , HEK293 Cells , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Protein Binding , Receptors, G-Protein-Coupled/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Small Molecule Libraries , Vero Cells
16.
J Clin Lab Anal ; 35(9): e23937, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1358069

ABSTRACT

OBJECTIVE: To deal with COVID-19, various countries have made many efforts, including the research and development of vaccines. The purpose of this manuscript was to summarize the development, application, and problems of COVID-19 vaccines. METHODS: This article reviewed the existing literature to see the development of the COVID-19 vaccine. RESULTS: We found that different types of vaccines had their own advantages and disadvantages. At the same time, the side effects of the vaccine, the dose of vaccination, the evaluation of the efficacy, and the application of the vaccine were all things worth studying. CONCLUSION: The successful development of the COVID-19 vaccine concerns almost all countries and people in the world. We must do an excellent job of researching the immunogenicity and immune reactivity of the vaccines. We hope this review can help colleagues at home and abroad.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/classification , Dose-Response Relationship, Drug , Drug Development/methods , Humans
17.
IEEE/ACM Trans Comput Biol Bioinform ; 18(4): 1290-1298, 2021.
Article in English | MEDLINE | ID: covidwho-1349906

ABSTRACT

An outbreak of COVID-19 that began in late 2019 was caused by a novel coronavirus(SARS-CoV-2). It has become a global pandemic. As of June 9, 2020, it has infected nearly 7 million people and killed more than 400,000, but there is no specific drug. Therefore, there is an urgent need to find or develop more drugs to suppress the virus. Here, we propose a new nonlinear end-to-end model called LUNAR. It uses graph convolutional neural networks to automatically learn the neighborhood information of complex heterogeneous relational networks and combines the attention mechanism to reflect the importance of the sum of different types of neighborhood information to obtain the representation characteristics of each node. Finally, through the topology reconstruction process, the feature representations of drugs and targets are forcibly extracted to match the observed network as much as possible. Through this reconstruction process, we obtain the strength of the relationship between different nodes and predict drug candidates that may affect the treatment of COVID-19 based on the known targets of COVID-19. These selected candidate drugs can be used as a reference for experimental scientists and accelerate the speed of drug development. LUNAR can well integrate various topological structure information in heterogeneous networks, and skillfully combine attention mechanisms to reflect the importance of neighborhood information of different types of nodes, improving the interpretability of the model. The area under the curve(AUC) of the model is 0.949 and the accurate recall curve (AUPR) is 0.866 using 10-fold cross-validation. These two performance indexes show that the model has superior predictive performance. Besides, some of the drugs screened out by our model have appeared in some clinical studies to further illustrate the effectiveness of the model.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Drug Evaluation, Preclinical/methods , Neural Networks, Computer , SARS-CoV-2/drug effects , COVID-19/epidemiology , Computational Biology , Databases, Pharmaceutical/statistics & numerical data , Drug Development/methods , Drug Development/statistics & numerical data , Drug Evaluation, Preclinical/statistics & numerical data , Drug Repositioning/methods , Drug Repositioning/statistics & numerical data , Host Microbial Interactions/drug effects , Humans , Nonlinear Dynamics , Pandemics
18.
Life Sci Alliance ; 4(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1346863

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for more than 3 million deaths in 219 countries across the world and with more than 140 million cases. The absence of FDA-approved drugs against SARS-CoV-2 has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and SARS-CoV-2 to provide insight into the virus' pathogenic mechanism and support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, first, in its healthy state. We then demonstrate how the entry of SARS-CoV-2 into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. A new computational method that predicts 20 unique reactions as drug targets from our models and provides a platform for future studies on viral entry inhibition, immune regulation, and drug optimisation strategies. The model is available in BioModels (https://www.ebi.ac.uk/biomodels/MODEL2007210001) and the software tool, findCPcli, that implements the computational method is available at https://github.com/findCP/findCPcli.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Drug Development/methods , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , COVID-19/epidemiology , Computational Biology/methods , Drug Evaluation, Preclinical/methods , Humans , Models, Biological , Pandemics
19.
Biomed Pharmacother ; 142: 112015, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1340558

ABSTRACT

COVID-19, an infectious disease, has emerged as one of the leading causes of death worldwide, making it one of the severe public health issues in recent decades. nCoV, the novel SARS coronavirus that causes COVID-19, has brought together scientists in the quest for possible therapeutic and preventive measures. The development of new drugs to manage COVID-19 effectively is a challenging and time-consuming process, thus encouraging extensive investigation of drug repurposing and repositioning candidates. Several medications, including remdesivir, hydroxychloroquine, chloroquine, lopinavir, favipiravir, ribavirin, ritonavir, interferons, azithromycin, capivasertib and bevacizumab, are currently under clinical trials for COVID-19. In addition, several medicinal plants with considerable antiviral activities are potential therapeutic candidates for COVID-19. Statistical data show that the pandemic is yet to slow down, and authorities are placing their hopes on vaccines. Within a short period, four types of vaccines, namely, whole virus, viral vector, protein subunit, and nucleic acid (RNA/DNA), which can confer protection against COVID-19 in different ways, were already in a clinical trial. SARS-CoV-2 variants spread is associated with antibody escape from the virus Spike epitopes, which has grave concerns for viral re-infection and even compromises the effectiveness of the vaccines. Despite these efforts, COVID-19 treatment is still solely based on clinical management through supportive care. We aim to highlight the recent trends in COVID-19, relevant statistics, and clinical findings, as well as potential therapeutics, including in-line treatment methods, preventive measures, and vaccines to combat the prevalence of COVID-19.


Subject(s)
Antiviral Agents , COVID-19 Vaccines , COVID-19/drug therapy , SARS-CoV-2/drug effects , Antiviral Agents/classification , Antiviral Agents/pharmacology , COVID-19/classification , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/classification , COVID-19 Vaccines/pharmacology , Drug Development/methods , Drug Discovery/methods , Drug Repositioning/methods , Humans
20.
Biomed Pharmacother ; 142: 111953, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1322006

ABSTRACT

Currently, there are over 230 different COVID-19 vaccines under development around the world. At least three decades of scientific development in RNA biology, immunology, structural biology, genetic engineering, chemical modification, and nanoparticle technologies allowed the accelerated development of fully synthetic messenger RNA (mRNA)-based vaccines within less than a year since the first report of a SARS-CoV-2 infection. mRNA-based vaccines have been shown to elicit broadly protective immune responses, with the added advantage of being amenable to rapid and flexible manufacturing processes. This review recapitulates current advances in engineering the first two SARS-CoV-2-spike-encoding nucleoside-modified mRNA vaccines, highlighting the strategies followed to potentiate their effectiveness and safety, thus facilitating an agile response to the current COVID-19 pandemic.


Subject(s)
Biomedical Engineering , COVID-19 Vaccines , COVID-19 , Drug Development/methods , Drug Discovery/methods , SARS-CoV-2 , Biomedical Engineering/methods , Biomedical Engineering/trends , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/classification , COVID-19 Vaccines/pharmacology , Drug Delivery Systems/methods , Humans , Immunogenicity, Vaccine , Liposomes/pharmacology , Nanoparticles , Nucleosides/pharmacology , Nucleosides/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/pharmacology
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