Natural products and SARS-CoV-2

Natural products have been proven to be the source of many antiviral drugs in the past. History has a bunch of natural products used as traditional medicine, therapies, mixtures, and oils. However, there are many bioactive natural products that need to be evaluated against severe acute respiratory syndrome (SARS-CoV-2) to curb the ongoing pandemic. Several plants and fungal-derived natural products are extensively reported with antiviral activities against SARS-CoV-2. In vitro, preliminary study assays and computational studies revealed several antiviral drugs from natural fungal compounds, including cordycepin isolated from Cordyceps militaris fungi. Polyphenolic compounds isolated from the Broussonetia papyrifera plant showed promising antiviral activity against SARS CoV-2 in in silico studies. Two alkaloid compounds, 10-hydroxyusambarensine and cryptoquindoline isolated from African medicinal plants, inhibited the main protease (Mpro) of SARS CoV-2. At the start of the COVID-19 pandemic, FDA approved the emergency use of chloroquine against SARS CoV-2;chloroquine is a derivative of alkaloid. The development of modern technologies has streamlined the discovery of new drugs from natural products. Gas chromatography–mass spectrometry, infrared radiation, nuclear magnetic resonance, high-performance thin-layer chromatography, and high-performance liquid chromatography and other high output technologies should be available for the structural interpretation and distinguishability of prudent lead molecules © 2023 Elsevier Inc. All rights reserved.

In silico prediction of natural compounds as potential multi-target inhibitors of structural proteins of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a colossal loss to human health and lives and has deeply impacted socio-economic growth. Remarkable efforts have been made by the scientific community in containing the virus by successful development of vaccines and diagnostic kits. Initiatives towards drug repurposing and discovery have also been undertaken. In this study, we compiled the known natural anti-viral compounds using text mining of the literature and examined them against four major structural proteins of SARS-CoV-2, namely, spike (S) protein, nucleocapsid (N) protein, membrane (M) protein and envelope (E) protein. Following computational approaches, we identified fangchinoline and versicolactone C as the compounds to exhibit strong binding to the target proteins and causing structural deformation of three structural proteins (N, S and M). We recommend the inhibitory effects of these compounds from our study should be experimentally validated against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Natural Products as Potential Therapeutic Agents for SARS-CoV-2: A Medicinal Chemistry Perspective.

Coronavirus is a single-stranded RNA virus discovered by virologist David Tyrrell in 1960. Till now seven human corona viruses have been identified including HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and SARS-CoV-2. In the present scenario, the SARS-CoV-2 outbreak causing SARS-CoV-2 pandemic, became the most serious public health emergency of the century worldwide. Natural products have long history and advantages for the drug discovery process. Almost 80% of drugs present in market are evolved from the natural resources. With the outbreak of SARS-CoV-2 pandemic, natural product chemists have made significant efforts for the identification of natural molecules which can be effective against the SARS-CoV-2. In current compilation we have discussed in vitro and in vivo anti-viral potential of natural product-based leads for the treatment of SARS-CoV-2. We have classified these leads in different classes of natural products such as alkaloids, terpenoids, flavonoids, polyphenols, quinones, cannabinoids, steroids, glucosinolates, diarylheptanoids, etc. and discussed the efficacy and mode of action of these natural molecules. The present review will surely opens new direction in future for the development of promising drug candidates particularly from the natural origin against coronaviruses and other viral diseases.

Molecular Analysis of Potential Inhibitors Against SARS-CoV-2: Computational Approach

SARS-CoV-2 has endangered the health of notable population of the world and hence, it attracted the attention of many researchers. In this study, we introduce two potential antiviral compounds for the treatment COVID-19 and compare it with the current reference drug. Molecular dynamics simulation and quantum theory of atoms in molecules (QTAIM) were used to study the host-guest interaction and dynamics between the nCov protein and inhibitors. Results obtained after a triplicate run of 100 ns for each compound revealed that compound B2 showed better inhibitory potential with MM-GBSA binding energy of -40.05 kcal mol-1, compared to the referenced drug. It is worth noting that B1 had a comparable binding potential with B2, suggesting some similarity in their inhibitory features. The QTAIM results showed that Laplacian ∇2ρ(r) and ellipticity (ε) were positive, indicating a stable protein-ligand interaction. The order of stability was in agreement with the MM-GBSA energy trends. The results showed that B1 and B2 can be used as a hopeful therapeutic for the cure of Covid-19. Though, a crucial trial should be done to authenticate this conclusion © 2023, Physical Chemistry Research. All Rights Reserved.

A Review of Bioactive Compounds against Porcine Enteric Coronaviruses.

Pig diarrhea is a universal problem in the process of pig breeding, which seriously affects the development of the pig industry. Porcine enteric coronaviruses (PECoVs) are common pathogens causing diarrhea in pigs, currently including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV). With the prosperity of world transportation and trade, the spread of viruses is becoming wider and faster, making it even more necessary to prevent PECoVs. In this paper, the host factors required for the efficient replication of these CoVs and the compounds that exhibit inhibitory effects on them were summarized to promote the development of drugs against PECoVs. This study will be also helpful in discovering general host factors that affect the replication of CoVs and provide references for the prevention and treatment of other CoVs.

Reactivity and binding mode of disulfiram, its metabolites, and derivatives in SARS-CoV-2 PLpro: insights from computational chemistry studies.

The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG‡ = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.

Suppression of SARS-CoV-2 Replication with Stabilized and Click-Chemistry Modified siRNAs.

The emergence of more transmissible or aggressive variants of SARS-CoV-2 requires the development of antiviral medication that is quickly adjustable to evolving viral escape mutations. Here we report the synthesis of chemically stabilized small interfering RNA (siRNA) against SARS-CoV-2. The siRNA can be further modified with receptor ligands such as peptides using CuI -catalysed click-chemistry. We demonstrate that optimized siRNAs can reduce viral loads and virus-induced cytotoxicity by up to five orders of magnitude in cell lines challenged with SARS-CoV-2. Furthermore, we show that an ACE2-binding peptide-conjugated siRNA is able to reduce virus replication and virus-induced apoptosis in 3D mucociliary lung microtissues. The adjustment of the siRNA sequence allows a rapid adaptation of their antiviral activity against different variants of concern. The ability to conjugate the siRNA via click-chemistry to receptor ligands facilitates the construction of targeted siRNAs for a flexible antiviral defence strategy.

In silico discovery of multi-targeting inhibitors for the COVID-19 treatment by molecular docking, molecular dynamics simulation studies, and ADMET predictions

Coronavirus disease-2019 (COVID-19), a global pandemic, has currently infected more than 247 million people around the world. Nowadays, several receptors of COVID-19 have been reported, and few of them are explored for drug discovery. New mutant strains of COVID-19 are emerging since the first outbreak of disease and causing significant morbidity and mortality across the world. Although, few drugs were approved for emergency uses, however, promising drug with well-proven clinical efficacy is yet to be discovered. Hence, researchers are continuously attempting to search for potential drug candidates targeting the well-established enzymatic targets of the virus. The present study aims to discover the antiviral compounds as potential inhibitors against the five targets in various stages of the SARS-CoV-2 life cycle, i.e., virus attachments (ACE2 and TMPRSS2), viral replication, and transcription (M-pro, PLpro and RdRp), using the most reliable molecular docking and molecular dynamics method. The ADMET study was then carried out to determine the pharmacokinetics and toxicity of several compounds with the best docking results. To provide a more effective mechanism for demonstrating protein-ligand interactions, molecular docking data were subjected to a molecular dynamic (MD) simulation at 300 K for 100 ns. In terms of structural stability, structure compactness, solvent accessible surface area, residue flexibility, and hydrogen bond interactions, the dynamic features of complexes have been compared.

Efficient One-Pot Synthesis of Indolhydroxy Derivatives Catalyzed by SnCl2, DFT Calculations and Docking Study

In this work we used an efficient and simple synthesis for the preparation of new indolhydroxy derivatives that has been performed by the reduction reaction of 2-nitrocinnamic acid or 2-nitrophenyl pyruvic acid with anhydrous stannous chloride (SnCl2) as a metal catalyst in different alcoholic solvents. During this transformation there was the involvement of intramolecular elimination cyclization. In the case of the reduction of 2-nitrocinnamic acid we obtained hydroxyindole plus hydroxyquinoline, on the other hand, the reduction of 2-nitrophenyl pyruvic acid gives hydroxyindole only, the products were obtained in suitable yields. The structures of all the synthesized compounds were fully characterized by different spectroscopic techniques such as 1H NMR, 13C NMR. In addition, the obtained products have been tested in silico against anti-human immunodeficiency virus type 1 (HIV-1) and SARS-CoV-2 virus. The outcomes of this work are very promising to develop more efficient antiviral compounds, indicating that these products may be a probable drugs for the SARS-CoV-2. © 2022, The Tunisian Chemical Society and Springer Nature Switzerland AG.

Deciphering the Interactions of SARS-CoV-2 Proteins with Human Ion Channels Using Machine-Learning-Based Methods.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for the protracted COVID-19 pandemic. Its high transmission rate and pathogenicity led to health emergencies and economic crisis. Recent studies pertaining to the understanding of the molecular pathogenesis of SARS-CoV-2 infection exhibited the indispensable role of ion channels in viral infection inside the host. Moreover, machine learning (ML)-based algorithms are providing a higher accuracy for host-SARS-CoV-2 protein-protein interactions (PPIs). In this study, PPIs of SARS-CoV-2 proteins with human ion channels (HICs) were trained on the PPI-MetaGO algorithm. PPI networks (PPINs) and a signaling pathway map of HICs with SARS-CoV-2 proteins were generated. Additionally, various U.S. food and drug administration (FDA)-approved drugs interacting with the potential HICs were identified. The PPIs were predicted with 82.71% accuracy, 84.09% precision, 84.09% sensitivity, 0.89 AUC-ROC, 65.17% Matthews correlation coefficient score (MCC) and 84.09% F1 score. Several host pathways were found to be altered, including calcium signaling and taste transduction pathway. Potential HICs could serve as an initial set to the experimentalists for further validation. The study also reinforces the drug repurposing approach for the development of host directed antiviral drugs that may provide a better therapeutic management strategy for infection caused by SARS-CoV-2.

Antiviral fungal metabolites and some insights into their contribution to the current COVID-19 pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, which started in late 2019, drove the scientific community to conduct innovative research to contain the spread of the pandemic and to care for those already affected. Since then, the search for new drugs that are effective against the virus has been strengthened. Featuring a relatively low cost of production under well-defined methods of cultivation, fungi have been providing a diversity of antiviral metabolites with unprecedented chemical structures. In this review, we present viral RNA infections highlighting SARS-CoV-2 morphogenesis and the infectious cycle, the targets of known antiviral drugs, and current developments in this area such as drug repurposing. We also explored the metabolic adaptability of fungi during fermentation to produce metabolites active against RNA viruses, along with their chemical structures, and mechanisms of action. Finally, the state of the art of research on SARS-CoV-2 inhibitors of fungal origin is reported, highlighting the metabolites selected by docking studies.

Engineering of Janus-Like Dendrimers with Peptides Derived from Glycoproteins of Herpes Simplex Virus Type 1: Toward a Versatile and Novel Antiviral Platform.

Novel antiviral nanotherapeutics, which may inactivate the virus and block it from entering host cells, represent an important challenge to face viral global health emergencies around the world. Using a combination of bioorthogonal copper-catalyzed 1,3-dipolar alkyne/azide cycloaddition (CuAAC) and photoinitiated thiol-ene coupling, monofunctional and bifunctional peptidodendrimer conjugates were obtained. The conjugates are biocompatible and demonstrate no toxicity to cells at biologically relevant concentrations. Furthermore, the orthogonal addition of multiple copies of two different antiviral peptides on the surface of a single dendrimer allowed the resulting bioconjugates to inhibit Herpes simplex virus type 1 at both the early and the late stages of the infection process. The presented work builds on further improving this attractive design to obtain a new class of therapeutics.

Evaluation of Microalgae Antiviral Activity and Their Bioactive Compounds.

During the last year, science has been focusing on the research of antivirally active compounds overall after the SARS-CoV-2 pandemic, which caused a great amount of deaths and the downfall of the economy in 2020. Photosynthetic organisms such as microalgae are known to be a reservoir of bioactive secondary metabolites; this feature, coupled with the possibility of achieving very high biomass levels without excessive energetic expenses, make microalgae worthy of attention in the search for new molecules with antiviral effects. In this work, the antiviral effects of microalgae against some common human or animal viruses were considered, focusing our attention on some possible effects against SARS-CoV-2. We summed up the data from the literature on microalgae antiviral compounds, from the most common ones, such as lectins, polysaccharides and photosynthetic pigments, to the less known ones, such as unidentified proteins. We have discussed the effects of a microalgae-based genetic engineering approach against some viral diseases. We have illustrated the potential antiviral benefits of a diet enriched in microalgae.

Can algae contribute to the war with Covid-19?

The world at large is facing a new threat with the emergence of the Coronavirus Disease 2019 (COVID-19) pandemic. Though imperceptible by the naked eye, the medical, sociological and economical implications caused by this newly discovered virus have been and will continue to be a great impediment to our lives. This health threat has already caused over two million deaths worldwide in the span of a year and its mortality rate is projected to continue rising. In this review, the potential of algae in combating the spread of COVID-19 is investigated since algal compounds have been tested against viruses and algal anti-inflammatory compounds have the potential to treat the severe symptoms of COVID-19. The possible utilization of algae in producing value-added products such as serological test kits, vaccines, and supplements that would either mitigate or hinder the continued health risks caused by the virus is prominent. Many of the characteristics in algae can provide insights on the development of microalgae to fight against SARS-CoV-2 or other viruses and contribute in manufacturing various green and high-value products.

The study of antiviral drugs targeting SARS-CoV-2 nucleocapsid and spike proteins through large-scale compound repurposing.

Contributing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clinical treatment, a drug library encompassing approximately 3,142 clinical-stage or FDA-approved small molecules is profiled to identify the candidate therapeutic inhibitors targeting nucleocapsid protein (N) and spike protein (S) of SARS-CoV-2. 16 screened candidates with higher binding affinity are evaluated via virtual screening. Comparing to those under trial/temporarily used antivirus drugs (i.e., umifenovir, lopinavir), ceftriaxone, cefotaxime, and cefuroxime show higher binding affinities to the N-terminal domain of N protein (N-NTD), C-terminal domain of N protein (N-CTD), and receptor-binding domain of S protein (S-RBD). Cefotaxime and cefuroxime have high binding affinities towards S-RBD with angiotensin-converting enzyme 2 (ACE2) complex via influence the critical interface sites at the interface of S-RBD (Arg403, Tyr453, Trp495, Gly496, Phe497, Asn501and Tyr505) and ACE2 (Asn33, His34, Glu37, Asp38, Lys353, Ala386, Ala387, Gln388, Pro389, Phe390 and Arg393) complex.

Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.

In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19.

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.

SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development.

The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.

anti-HCoV: A web resource to collect natural compounds against human coronaviruses.

BACKGROUND: A novel coronavirus, the SARS-CoV2, was revealed to be the cause of COVID19, the pandemic disease that already provoked more than 555.324 deaths in the world (July 10, 2020). No vaccine treatment has been defined against SARS-CoV2 or other human coronaviruses (HCoVs), including those causing epidemic infections, neither appropriate strategies for prevention and care are yet officially suggested. SCOPE AND APPROACH: We reviewed scientific literature on natural compounds that were defined as potentially effective against human coronaviruses. Our desk research identified non-chemically modified natural compounds that were shown (in vitro) and/or predicted (in silico) to act against one or more phases of human coronaviruses cell cycle.We selected all available information, merged and annotated the data to define a comprehensive list of natural compounds, describing their chemical classification, the source, the action, the specific target in the viral infection. Our aim was to collect possible compounds for prevention and care against human coronaviruses. KEY FINDINGS AND CONCLUSIONS: The definition of appropriate interventions against viral diseases need a comprehensive view on the infection dynamics and on necessary treatments. Viral targeting compounds to be exploited in food sciences could be of relevant interest to this aim.We collected 174 natural compounds showing effects against human infecting coronaviruses, providing a curated annotation on actions and targets.The data are available in anti-HCoV, a web accessible resource to be exploited for testing and in vivo trials. The website is here launched to favour a community based cooperative effort to call for contribution and expand the collection. To be ready to fight.

Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study.

The aim of this study was to develop an appropriate anti-viral drug against the SARS-CoV-2 virus. An immediately qualifying strategy would be to use existing powerful drugs from various virus treatments. The strategy in virtual screening of antiviral databases for possible therapeutic effect would be to identify promising drug molecules, as there is currently no vaccine or treatment approved against COVID-19. Targeting the main protease (pdb id: 6LU7) is gaining importance in anti-CoV drug design. In this conceptual context, an attempt has been made to suggest an in silico computational relationship between US-FDA approved drugs, plant-derived natural drugs, and Coronavirus main protease (6LU7) protein. The evaluation of results was made based on Glide (Schrödinger) dock score. Out of 62 screened compounds, the best docking scores with the targets were found for compounds: lopinavir, amodiaquine, and theaflavin digallate (TFDG). Molecular dynamic (MD) simulation study was also performed for 20 ns to confirm the stability behaviour of the main protease and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders.