Elucidation on the Physicochemical Properties of Potential and Clinically Approved Antiviral Drugs: A Search for Effective Therapies against SARS-CoV-2 Infection

COVID-19 has been confirmed in millions of individuals worldwide, rendering it a global medical emergency. In the absence of vaccines and the unavailability of effective drugs for the SARS-CoV-2 infection, vaccine development is being continuously explored and several antiviral compounds and immunotherapies are currently being investigated. Given the high similarity in genetic identity between SARS-CoV and SARS-CoV-2, the present investigation identified the interaction between the physicochemical properties and the antiviral activity of different potential and clinically approved antiviral drugs against SARS-CoV using hierarchically weighted principal component analysis. Representative drugs from the classes of neuraminidase inhibitors, reverse transcriptase inhibitors, protease inhibitors, nucleoside analogues, and other compounds with potential antiviral activity were examined. The pharmacologic classification and the biological activity of the different antiviral drugs were described using indices, namely, rotatable bond count, molecular weight, heavy atom count, and molecular complexity (92.32% contribution rate). The physicochemical properties and inhibitory action against SARS-CoV-2 of lopinavir, chloroquine, ivermectin, and ciclesonide validated the adequacy of the current computational approach. The findings of the present study provide additional information, although further investigation is warranted to identify potential targets and establish exact mechanisms, in the emergent search and design of antiviral drug candidates and their subsequent synthesis as effective therapies for COVID-19.

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Diverse Effects of Exosomes on COVID-19: A Perspective of Progress From Transmission to Therapeutic Developments

Frontiers in Immunology ◽

10.3389/fimmu.2021.716407 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sangiliyandi Gurunathan ◽

Min Hee Kang ◽

Jin-Hoi Kim

Keyword(s):

Vaccine Development ◽

Antiviral Drug ◽

Treatment Strategies ◽

Antiviral Drugs ◽

Therapeutic Benefits ◽

Global Pandemic ◽

Lung Injuries ◽

Infected Cells ◽

Intercellular Spread

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus and the causative agent of the current global pandemic of coronavirus disease 2019 (COVID-19). There are currently no FDA-approved antiviral drugs for COVID-19 and there is an urgent need to develop treatment strategies that can effectively suppress SARS-CoV-2 infection. Numerous approaches have been researched so far, with one of them being the emerging exosome-based therapies. Exosomes are nano-sized, lipid bilayer-enclosed structures, share structural similarities with viruses secreted from all types of cells, including those lining the respiratory tract. Importantly, the interplay between exosomes and viruses could be potentially exploited for antiviral drug and vaccine development. Exosomes are produced by virus-infected cells and play crucial roles in mediating communication between infected and uninfected cells. SARS-CoV-2 modulates the production and composition of exosomes, and can exploit exosome formation, secretion, and release pathways to promote infection, transmission, and intercellular spread. Exosomes have been exploited for therapeutic benefits in patients afflicted with various diseases including COVID-19. Furthermore, the administration of exosomes loaded with immunomodulatory cargo in combination with antiviral drugs represents a novel intervention for the treatment of diseases such as COVID-19. In particular, exosomes derived from mesenchymal stem cells (MSCs) are used as cell-free therapeutic agents. Mesenchymal stem cell derived exosomes reduces the cytokine storm and reverse the inhibition of host anti-viral defenses associated with COVID-19 and also enhances mitochondrial function repair lung injuries. We discuss the role of exosomes in relation to transmission, infection, diagnosis, treatment, therapeutics, drug delivery, and vaccines, and present some future perspectives regarding their use for combating COVID-19.

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Identification of African Swine Fever Virus Inhibitors through High Performance Virtual Screening Using Machine Learning

International Journal of Molecular Sciences ◽

10.3390/ijms222413414 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13414

Author(s):

Jiwon Choi ◽

Dongseob Tark ◽

Yun-Sook Lim ◽

Soon B. Hwang

Keyword(s):

Machine Learning ◽

High Performance ◽

African Swine Fever Virus ◽

Antiviral Drug ◽

African Swine Fever ◽

Principal Component ◽

Antiviral Drugs ◽

Fever Virus ◽

Scoring Functions

African swine fever virus (ASFV) is a highly contagious virus that causes severe hemorrhagic viral disease resulting in high mortality in domestic and wild pigs, until few antiviral agents can inhibit ASFV infections. Thus, new anti-ASFV drugs need to be urgently identified. Recently, we identified pentagastrin as a potential antiviral drug against ASFVs using molecular docking and machine learning models. However, the scoring functions are easily influenced by properties of protein pockets, resulting in a scoring bias. Here, we employed the 5′-P binding pocket of AsfvPolX as a potential binding site to identify antiviral drugs and classified 13 AsfvPolX structures into three classes based on pocket parameters calculated by the SiteMap module. We then applied principal component analysis to eliminate this scoring bias, which was effective in making the SP Glide score more balanced between 13 AsfvPolX structures in the dataset. As a result, we identified cangrelor and fostamatinib as potential antiviral drugs against ASFVs. Furthermore, the classification of the pocket properties of AsfvPolX protein can provide an alternative approach to identify novel antiviral drugs by optimizing the scoring function of the docking programs. Here, we report a machine learning-based novel approach to generate high binding affinity compounds that are individually matched to the available classification of the pocket properties of AsfvPolX protein.

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Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture

10.1101/2020.10.30.362335 ◽

2020 ◽

Author(s):

Yanmei Hu ◽

Chunlong Ma ◽

Tommy Szeto ◽

Brett Hurst ◽

Bart Tarbet ◽

...

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Cathepsin L ◽

Antiviral Drug ◽

Antiviral Effect ◽

Neutralization Assay ◽

Drug Candidates ◽

Main Protease ◽

Human Coronaviruses ◽

Calpain Inhibitors

AbstractAs the COVID-19 pandemic continues to fold out, the morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four SARS-CoV-2 main protease (Mpro) inhibitors including boceprevir, calpain inhibitors II and XII and GC-376 with potent antiviral activity against infectious SARS-CoV-2 in cell culture. Despite the weaker enzymatic inhibition of calpain inhibitors II and XII against Mpro compared to GC-376, calpain inhibitors II and XII had more potent cellular antiviral activity. This observation promoted us to hypothesize that the cellular antiviral activity of calpain inhibitors II and XII might also involve the inhibition of cathepsin L in addition to Mpro. To test this hypothesis, we tested calpain inhibitors II and XII in the SARS-CoV-2 pseudovirus neutralization assay in Vero E6 cells and found that both compounds significantly decreased pseudoviral particle entry into cells, indicating their role in inhibiting cathepsin L. The involvement of cathepsin L was further confirmed in the drug time-of-addition experiment. In addition, we found that these four compounds not only inhibit SARS-CoV-2, but also SARS-CoV, MERS-CoV, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. The mechanism of action is through targeting the viral Mpro, which was supported by the thermal shift binding assay and enzymatic FRET assay. We further showed that these four compounds have additive antiviral effect when combined with remdesivir. Altogether, these results suggest that boceprevir, calpain inhibitors II and XII, and GC-376 are not only promising antiviral drug candidates against existing human coronaviruses, but also might work against future emerging CoVs.

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Antiviral Activity of CD437 Against Mumps Virus

Frontiers in Microbiology ◽

10.3389/fmicb.2021.751909 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fumihiro Kato ◽

Yuichiro Nakatsu ◽

Keiko Murano ◽

Aika Wakata ◽

Toru Kubota ◽

...

Keyword(s):

Antiviral Activity ◽

Fluorescent Protein ◽

Screening Method ◽

Antiviral Drug ◽

Mumps Virus ◽

Screening Methods ◽

Drug Candidates ◽

Late Step ◽

Key Factor ◽

Green Fluorescent

Many efforts have been dedicated to the discovery of antiviral drug candidates against the mumps virus (MuV); however, no specific drug has yet been approved. The development of efficient screening methods is a key factor for the discovery of antiviral candidates. In this study, we evaluated a screening method using an Aequorea coerulescens green fluorescent protein-expressing MuV infectious molecular clone. The application of this system to screen for active compounds against MuV replication revealed that CD437, a retinoid acid receptor agonist, has anti-MuV activity. The point of antiviral action was a late step(s) in the MuV life cycle. The replication of other paramyxoviruses was also inhibited by CD437. The induction of retinoic acid-inducible gene (RIG)-I expression is a reported mechanism for the antiviral activity of retinoids, but our results indicated that CD437 did not stimulate RIG-I expression. Indeed, we observed antiviral activity despite the absence of RIG-I, suggesting that CD437 antiviral activity does not require RIG-I induction.

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ENNAVIA is an innovative new method which employs neural networks for antiviral and anti-coronavirus activity prediction for therapeutic peptides

10.1101/2021.03.25.436982 ◽

2021 ◽

Author(s):

Patrick Brendan Timmons ◽

Chandralal M. Hewage

Keyword(s):

In Silico ◽

Antiviral Drug ◽

Area Under The Curve ◽

Antiviral Drugs ◽

Test Accuracy ◽

Sequencing Data ◽

Drug Candidates ◽

Therapeutic Peptides ◽

Antiviral Activities ◽

External Test

AbstractViruses represent one of the greatest threats to human health, necessitating the development of new antiviral drug candidates. Antiviral peptides often possess excellent biological activity and a favourable toxicity profile, and therefore represent a promising field of novel antiviral drugs. As the quantity of sequencing data grows annually, the development of an accurate in silico method for the prediction of peptide antiviral activities is important. This study leverages advances in deep learning and cheminformatics to produce a novel sequence-based deep neural network classifier for the prediction of antiviral peptide activity. The method out-performs the existent best-in-class, with an external test accuracy of 93.9%, Matthews correlation coefficient of 0.87 and an Area Under the Curve of 0.93 on the dataset of experimentally validated peptide activities. This cutting-edge classifier is available as an online web server at https://research.timmons.eu/ennavia, facilitating in silico screening and design of peptide antiviral drugs by the wider research community.

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New Chalcone Derivatives as Effective Anti-SARS-CoV-2 Agents

10.21203/rs.3.rs-515050/v1 ◽

2021 ◽

Author(s):

Nizami Duran ◽

M. Fatih Polat ◽

Derya Anil Aktas ◽

M. Abdullah Alagoz ◽

Emrah Ay ◽

...

Keyword(s):

Antiviral Activity ◽

Antiviral Drug ◽

Rt Pcr ◽

Chalcone Derivatives ◽

Drug Candidates ◽

Angelica Keiskei ◽

Antiviral Activities ◽

Computational Analyses ◽

Dose Dependent ◽

Related Compounds

Abstract Flavonoids and related compounds, such as quercetin-based antiviral drug Gene-Eden-VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus (SARS-CoV-2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS-CoV proteases. Hydroxychloroquine and Favipiravir have been used in many countries since the beginning of the pandemic with the thought that they may have antiviral activity against SARS CoV-2. In this study, we aimed to compare the anti-SARS CoV-2 activities of both newly synthesized chalcone derivatives and these two drugs.The current study aimed to determine the potent antiviral activity of newly synthesized chalcone derivatives against SARS-CoV-2 by calculating the RT-PCR cycling threshold (Ct) values. Antiviral activities of the compounds varied due to being dose dependent. Compound 6, 7, 9 and 16 were highly effective against SARS-CoV-2 at concentrations of 1.60 µg/mL. Structure-based virtual screening was carried out against the most important druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase (RdRp), to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from − 4,370 to -2,748 kcal/mol along with their toxicological, ADME, and drug-like properties.

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NANOPARTICLE AS THE STRATEGY FOR THE DEVELOPMENT OF SARS-COV-2 ANTIVIRAL DRUGS

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i5.42604 ◽

2021 ◽

pp. 33-43

Author(s):

SRI HARTATI YULIANI

Keyword(s):

Antiviral Drug ◽

Drug Repurposing ◽

Antiviral Drugs ◽

Nanostructured Lipid Carrier ◽

Solid Lipid Nanoparticle ◽

Metallic Nanoparticle ◽

Drug Candidates ◽

Polymeric Nanoparticle ◽

Nanoparticle System ◽

Selection Of

In just a matter of months, SARS-CoV-2 had spread around the world. Scientists collaborate to solve the problem. The development of antiviral drugs is a challenge in itself due to the rapidly changing nature of the virus. Selection of drug candidates can be done quickly through the repurposing drug method. Broad-spectrum antiviral drugs may be strong candidates for SARS-CoV-2 therapy. Nanotechnology is one solution in the development of antiviral drug delivery systems. The advantages possessed by the nanoparticle system can answer the need for an ideal antiviral drug. This article will focus on the development of nanoparticle preparations as a strategy in handling viruses, including SARS-CoV-2. The selection of article for the current review was searched from specialized databases such as Elsevier, Pubmed, Science Direct, Medscape and other credible databases using the keywords nanoparticle, SARS-CoV-2, Covid-19, drug repurposing, polymeric nanoparticle, micelle, liposome, solid lipid nanoparticle, nanostructured lipid carrier, dendrimer, metallic nanoparticle. The range of articles was 2007–2021.

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Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

10.1101/2021.04.13.439274 ◽

2021 ◽

Author(s):

Michael Sugiyama ◽

Haotian Cui ◽

Dar'ya S Redka ◽

Mehran Karimzadeh ◽

Edurne Rujas ◽

...

Keyword(s):

Antiviral Activity ◽

Drug Targets ◽

Antiviral Drug ◽

Drug Repurposing ◽

Human Coronavirus ◽

Independent Manner ◽

Drug Candidates ◽

Convolutional Networks ◽

Target Drug ◽

Coronavirus Infection

The COVID-19 pandemic has led to an urgent need for the identification of new antiviral drug therapies that can be rapidly deployed to treat patients with this disease. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of COVID-19. 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 repurposing drug 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.

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A Review of Medicinal Plants with Antiviral Activity Available in Bangladesh and Mechanistic Insight Into Their Bioactive Metabolites on SARS-CoV-2, HIV and HBV

Frontiers in Pharmacology ◽

10.3389/fphar.2021.732891 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sitesh C. Bachar ◽

Kishor Mazumder ◽

Ritesh Bachar ◽

Asma Aktar ◽

Mamun Al Mahtab

Keyword(s):

Medicinal Plants ◽

Antiviral Activity ◽

Oleanolic Acid ◽

Bioactive Compounds ◽

In Silico ◽

Hepatitis Virus ◽

Antiviral Drug ◽

Antiviral Drugs ◽

Bioactive Metabolites ◽

Antiviral Activities

Currently, viral infection is the most serious health issue which causing unexpected higher rate of death globally. Many viruses are not yet curable, such as corona virus-2 (SARS-CoV-2), human immunodeficiency virus (HIV), hepatitis virus, human papilloma virus and so others. Furthermore, the toxicities and ineffective responses to resistant strains of synthetic antiviral drugs have reinforced the search of effective and alternative treatment options, such as plant-derived antiviral drug molecules. Therefore, in the present review, an attempt has been taken to summarize the medicinal plants reported for exhibiting antiviral activities available in Bangladesh along with discussing the mechanistic insights into their bioactive components against three most hazardous viruses, namely SARS-CoV-2, HIV, and HBV. The review covers 46 medicinal plants with antiviral activity from 25 families. Among the reported 79 bioactive compounds having antiviral activities isolated from these plants, about 37 of them have been reported for significant activities against varieties of viruses. Hesperidin, apigenin, luteolin, seselin, 6-gingerol, humulene epoxide, quercetin, kaempferol, curcumin, and epigallocatechin-3-gallate (EGCG) have been reported to inhibit multiple molecular targets of SARS-CoV-2 viral replication in a number of in silico investigations. Besides, numerous in silico, in vitro, and in vivo bioassays have been demonstrated that EGCG, anolignan-A, and B, ajoene, curcumin, and oleanolic acid exhibit anti-HIV activity while piperine, ursolic acid, oleanolic acid, (+)-cycloolivil-4′-O-β-d-glucopyranoside, quercetin, EGCG, kaempferol, aloin, apigenin, rosmarinic acid, andrographolide, and hesperidin possess anti-HBV activity. Thus, the antiviral medicinal plants and the isolated bioactive compounds may be considered for further advanced investigations with the aim of the development of effective and affordable antiviral drugs.

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Development and Effects of Influenza Antiviral Drugs

Molecules ◽

10.3390/molecules26040810 ◽

2021 ◽

Vol 26 (4) ◽

pp. 810

Author(s):

Hang Yin ◽

Ning Jiang ◽

Wenhao Shi ◽

Xiaojuan Chi ◽

Sairu Liu ◽

...

Keyword(s):

Antiviral Activity ◽

Plant Extracts ◽

Influenza A ◽

Antiviral Drug ◽

Antiviral Drugs ◽

High Morbidity ◽

Promising Alternative ◽

Microbial Extracts ◽

Strong Antiviral Activity ◽

Drug Resistant Virus

Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.

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