Hesperidin for COVID-19

The coronavirus disease 2019 (COVID-19) is a severe worldwide pandemic. Due to the emergence of various SARS-CoV-2 variants and the presence of only one Food and Drug Administration (FDA) approved anti-COVID-19 drug (remdesivir), the disease remains a mindboggling global public health problem. Developing anti-COVID-19 drug candidates that are effective against SARS-CoV-2 and its various variants is a pressing need that should be satisfied. This systematic review assesses the existing literature that used in silico models during the discovery procedure of anti-COVID-19 drugs. Cochrane Library, Science Direct, Google Scholar, and PubMed were used to conduct a literature search to find the relevant articles utilizing the search terms “In silico model,” “COVID-19,” “Anti-COVID-19 drug,” “Drug discovery,” “Computational drug designing,” and “Computer-aided drug design.” Studies published in English between 2019 and December 2022 were included in the systematic review. From the 1120 articles retrieved from the databases and reference lists, only 33 were included in the review after the removal of duplicates, screening, and eligibility assessment. Most of the articles are studies that use SARS-CoV-2 proteins as drug targets. Both ligand-based and structure-based methods were utilized to obtain lead anti-COVID-19 drug candidates. Sixteen articles also assessed absorption, distribution, metabolism, excretion, toxicity (ADMET), and drug-likeness properties. Confirmation of the inhibitory ability of the candidate leads by in vivo or in vitro assays was reported in only five articles. Virtual screening, molecular docking (MD), and molecular dynamics simulation (MDS) emerged as the most commonly utilized in silico models for anti-COVID-19 drug discovery.

The ongoing COVID-19 pandemic has resulted in a global panic because of its continual evolution and recurring spikes. This serious malignancy is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak, millions of people have been affected from December 2019 till now, which has led to a great surge in finding treatments. Despite trying to handle the pandemic with the repurposing of some drugs, such as chloroquine, hydroxychloroquine, remdesivir, lopinavir, ivermectin, etc., against COVID-19, the SARS-CoV-2 virus continues its out-of-control spread. There is a dire need to identify a new regimen of natural products to combat the deadly viral disease. This article deals with the literature reports to date of natural products showing inhibitory activity towards SARS-CoV-2 through different approaches, such as in vivo, in vitro, and in silico studies. Natural compounds targeting the proteins of SARS-CoV-2—the main protease (Mpro), papain-like protease (PLpro), spike proteins, RNA-dependent RNA polymerase (RdRp), endoribonuclease, exoribonuclease, helicase, nucleocapsid, methyltransferase, adeno diphosphate (ADP) phosphatase, other nonstructural proteins, and envelope proteins—were extracted mainly from plants, and some were isolated from bacteria, algae, fungi, and a few marine organisms.

AbstractThe recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify Mpro inhibitors and potential novel compound scaffolds against SARS-CoV-2. The screen revealed a heterogeneous set of 692 potential Mpro inhibitors containing known ones such as Dasatinib, Amodiaquine, and Flavin mononucleotide, as well as so far untested chemical scaffolds. In a follow-up evaluation, we used publicly available data published almost two years after the screen to validate our results. In total, we are able to validate 17% of the top 100 predictions with publicly available data and can furthermore show that predicted compounds do cover scaffolds that are yet not associated with Mpro. Finally, we detected a potentially important binding pattern consisting of 3 hydrogen bonds with hydrogen donors of an oxyanion hole within the active side of Mpro. Overall, these results give hope that we will be better prepared for future pandemics and that drug development will become more efficient in the upcoming years.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.

According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine’s effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.

COVID-19 pandemic caused by the novel SARS-CoV-2 has impacted human livelihood globally. Strenuous efforts have been employed for its control and prevention; however, with recent reports on mutated strains with much higher infectivity, transmissibility, and ability to evade immunity developed from previous SARS-CoV-2 infections, prevention alternatives must be prepared beforehand in case. We have perused over 128 recent works (found on Google Scholar, PubMed, and ScienceDirect as of February 2023) on medicinal plants and their compounds for anti-SARS-CoV-2 activity and eventually reviewed 102 of them. The clinical application and the curative effect were reported high in China and in India. Accordingly, this review highlights the unprecedented opportunities offered by medicinal plants and their compounds, candidates as the therapeutic agent, against COVID-19 by acting as viral protein inhibitors and immunomodulator in (32 clinical trials and hundreds of in silico experiments) conjecture with modern science. Moreover, the associated foreseeable challenges for their viral outbreak management were discussed in comparison to synthetic drugs.

In the present study, we investigated the antiviral activities of 17 flavonoids as natural products. These derivatives were evaluated for their in vitro antiviral activities against HIV and SARS-CoV-2. Their antiviral activity was evaluated for the first time based on POM (Petra/Osiris/Molispiration) theory and docking analysis. POM calculation was used to analyze the atomic charge and geometric characteristics. The side effects, drug similarities, and drug scores were also assumed for the stable structure of each compound. These results correlated with the experimental values. The bioinformatics POM analyses of the relative antiviral activities of these derivatives are reported for the first time.

Natural products and plant extracts exhibit many biological activities, including that related to the defense mechanisms against parasites. Many studies have investigated the biological functions of secondary metabolites and reported evidence of antiviral activities. The pandemic emergencies have further increased the interest in finding antiviral agents, and efforts are oriented to investigate possible activities of secondary plant metabolites against human viruses and their potential application in treating or preventing SARS-CoV-2 infection. In this review, we performed a comprehensive analysis of studies through in silico and in vitro investigations, also including in vivo applications and clinical trials, to evaluate the state of knowledge on the antiviral activities of secondary metabolites against human viruses and their potential application in treating or preventing SARS-CoV-2 infection, with a particular focus on natural compounds present in food plants. Although some of the food plant secondary metabolites seem to be useful in the prevention and as a possible therapeutic management against SARS-CoV-2, up to now, no molecules can be used as a potential treatment for COVID-19; however, more research is needed.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a profound impact on the world’s health and economy. Although the end of the pandemic may come in 2023, it is generally believed that the virus will not be completely eradicated. Most likely, the disease will become an endemicity. The rapid development of vaccines of different types (mRNA, subunit protein, inactivated virus, etc.) and some other antiviral drugs (Remdesivir, Olumiant, Paxlovid, etc.) has provided effectiveness in reducing COVID-19’s impact worldwide. However, the circulating SARS-CoV-2 virus has been constantly mutating with the emergence of multiple variants, which makes control of COVID-19 difficult. There is still a pressing need for developing more effective antiviral drugs to fight against the disease. Plants have provided a promising production platform for both bioactive chemical compounds (small molecules) and recombinant therapeutics (big molecules). Plants naturally produce a diverse range of bioactive compounds as secondary metabolites, such as alkaloids, terpenoids/terpenes and polyphenols, which are a rich source of countless antiviral compounds. Plants can also be genetically engineered to produce valuable recombinant therapeutics. This molecular farming in plants has an unprecedented opportunity for developing vaccines, antibodies, and other biologics for pandemic diseases because of its potential advantages, such as low cost, safety, and high production volume. This review summarizes the latest advancements in plant-derived drugs used to combat COVID-19 and discusses the prospects and challenges of the plant-based production platform for antiviral agents.

The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly exert antiviral activities, such as the inhibition of virus invasion and the replication and inhibition of viral proteases. In addition, flavonoids can modulate the levels of interferon and proinflammatory factors. We have reviewed the previously reported relevant literature researching the pharmacological anti-SARS-CoV-2 activity of flavonoids where structures, classifications, synthetic pathways, and pharmacological effects are summarized. There is no doubt that flavonoids have great potential in the treatment of COVID-19. However, most of the current research is still in the theoretical stage. More studies are recommended to evaluate the efficacy and safety of flavonoids against SARS-CoV-2.

Since the outbreak of the COVID-19 (coronavirus disease 19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). The present study aimed to evaluate bioactive compounds found in plants using a molecular docking approach to inhibit the main protease (Mpro) and spike (S) glycoprotein of SARS-CoV-2. The evaluation was performed on the docking scores calculated using AutoDock Vina (AV) as a docking engine. A rule of five (Ro5) was calculated to determine whether a compound meets the criteria as an active drug orally in humans. The determination of the docking score was performed by selecting the best conformation of the protein-ligand complex that had the highest affinity (most negative Gibbs’ free energy of binding/ <math xmlns="http://www.w3.org/1998/Math/MathML" id="M1"> <mi mathvariant="normal">Δ</mi> <mi>G</mi> </math> ). As a comparison, nelfinavir (an antiretroviral drug), chloroquine, and hydroxychloroquine sulfate (antimalarial drugs recommended by the FDA as emergency drugs) were used. The results showed that hesperidin, nabiximols, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine, and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and nabiximols had about the same pose as nelfinavir but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. This finding implied that several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine, and hydroxychloroquine sulfate, which so far are recommended in the treatment of COVID-19. From quantum chemical DFT calculations, the ascending order of chemical reactivity of selected compounds was pectolinarin &gt; hesperidin &gt; rhoifolin &gt; morin &gt; epigallocatechin gallate. All isolated compounds’ C=O regions are preferable for an electrophilic attack, and O-H regions are suitable for a nucleophilic attack. Furthermore, Homo-Lumo and global descriptor values indicated a satisfactory remarkable profile for the selected compounds. As judged by the RO5 and previous study by others, the compounds kaempferol, herbacetin, eugenol, and 6-shogaol have good oral bioavailability, so they are also seen as promising candidates for the development of drugs to treat infections caused by SARS-CoV-2. The present study identified plant-based compounds that can be further investigated in vitro and in vivo as lead compounds against SARS-CoV-2.

COVID-19 pandemic is a serious problem in the world today. The SARS-CoV-2 virus that causes COVID-19 has important proteins used for its infection and development, namely the protease and spike glycoprotein. The RBD (Receptor Binding Domain) of spike glycoprotein (RBD-S) can bind to the ACE2 (Angiotensin Converting Enzyme-2) receptor at the protease domain (PD) (PD-ACE2) of the host cell, thereby leading to a viral infection. This study aims to reveal the potential of compounds contained in Curcuma sp., Citrus sp., Alpinia galanga, and Caesalpinia sappan as anti SARS-CoV-2 through its binding to 3 protein receptors. The study was conducted by molecular docking using the MOE 2010 program (licensed from Faculty of Pharmacy UGM, Indonesia). The selected protein targets are RBD-S (PDB ID:6LXT), PD-ACE2 (PDB ID: 6VW1), and SARS-CoV-2 protease (PDB ID:6LU7). The affinities of bonds formed is represented as a docking score. The results show that hesperidin, one of the compounds in Citrus sp., has the lowest docking score for all three protein receptors representing the highest affinity to bind the receptors. Moreover, all of the citrus flavonoids possess good affinity to the respected receptors as well as curcumin, brazilin, and galangin, indicating that those compounds perform inhibitory potential for the viral infection and replication. In general, the results of this study indicate that Citrus sp. exhibit the best potential as an inhibitor to the development of the SARS-CoV-2, followed by galangal, sappan wood, and Curcuma sp. that can be consumed in daily life as prophylaxis of COVID-19.

The recent pandemic of COVID-19 caused by the SARS-CoV-2 virus has brought upon the world an unprecedented challenge. During its acute dissemination, a rush for vaccines started, making the scientific community come together and contribute to the development of efficient therapeutic agents and vaccines. Natural products have been used as sources of individual molecules and extracts capable of inhibiting/neutralizing several microorganisms, including viruses. Natural extracts have shown effective results against the coronavirus family, when first tested in the outbreak of SARS-CoV-1, back in 2002. In this review, the relationship between natural extracts and SARS-CoV is discussed, while also providing insight into misinformation regarding the use of plants as possible therapeutic agents. Studies with plant extracts on coronaviruses are presented, as well as the main inhibition assays and trends for the future regarding the yet unknown long-lasting effects post-infection with SARS-CoV-2.