Theaflavin for COVID-19

The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.

AbstractCOVID‐19, which was first identified in 2019 in Wuhan, China, is a respiratory illness caused by a virus called severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Although some patients infected with COVID‐19 can remain asymptomatic, most experience a range of symptoms that can be mild to severe. Common symptoms include fever, cough, shortness of breath, fatigue, loss of taste or smell and muscle aches. In severe cases, complications can arise including pneumonia, acute respiratory distress syndrome, organ failure and even death, particularly in older adults or individuals with underlying health conditions. Treatments for COVID‐19 include remdesivir, which has been authorised for emergency use in some countries, and dexamethasone, a corticosteroid used to reduce inflammation in severe cases. Biological drugs including monoclonal antibodies, such as casirivimab and imdevimab, have also been authorised for emergency use in certain situations. While these treatments have improved the outcome for many patients, there is still an urgent need for new treatments. Medicinal plants have long served as a valuable source of new drug leads and may serve as a valuable resource in the development of COVID‐19 treatments due to their broad‐spectrum antiviral activity. To date, various medicinal plant extracts have been studied for their cellular and molecular interactions, with some demonstrating anti‐SARS‐CoV‐2 activity in vitro. This review explores the evaluation and potential therapeutic applications of these plants against SARS‐CoV‐2. This review summarises the latest evidence on the activity of different plant extracts and their isolated bioactive compounds against SARS‐CoV‐2, with a focus on the application of plant‐derived compounds in animal models and in human studies.

Background: As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp. Methods: A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2. Results: Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings. Conclusions: Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates.

The COVID-19 pandemic has stimulated collaborative drug discovery efforts in academia and the industry with the aim of developing therapies and vaccines that target SARS-CoV-2. Several novel therapies have been approved and deployed in the last three years. However, their clinical application has revealed limitations due to the rapid emergence of viral variants. Therefore, the development of next-generation SARS-CoV-2 therapeutic agents with a high potency and safety profile remains a high priority for global health. Increasing awareness of the “back to nature” approach for improving human health has prompted renewed interest in natural products, especially dietary polyphenols, as an additional therapeutic strategy to treat SARS-CoV-2 patients, owing to its good safety profile, exceptional nutritional value, health-promoting benefits (including potential antiviral properties), affordability, and availability. Herein, we describe the biological properties and pleiotropic molecular mechanisms of dietary polyphenols curcumin, resveratrol, and gossypol as inhibitors against SARS-CoV-2 and its variants as observed in in vitro and in vivo studies. Based on the advantages and disadvantages of dietary polyphenols and to obtain maximal benefits, several strategies such as nanotechnology (e.g., curcumin-incorporated nanofibrous membranes with antibacterial-antiviral ability), lead optimization (e.g., a methylated analog of curcumin), combination therapies (e.g., a specific combination of plant extracts and micronutrients), and broad-spectrum activities (e.g., gossypol broadly inhibits coronaviruses) have also been emphasized as positive factors in the facilitation of anti-SARS-CoV-2 drug development to support effective long-term pandemic management and control.

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.

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.

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.

Plant species with anti-inflammatory properties might play an essential role in combatting COVID-19 via reducing cytokine storms. We aimed to review the extant evidence of the potential therapeutic efficacy of natural products against cytokine storms by inhibiting interleukin-6 (IL-6) as a major pathological mediator. Data were collected following an electronic search in major databases (Pubmed, Scopus, Web of Science, Google Scholar) and also preprint articles on preprint and medRxiv servers by using a combination of relevant keywords. Seventeen active compounds and medicinal plants were found and reviewed in the present review. Results of both in-vivo and in-vitro experiments conducted on these compounds showed that Phillyrin, SMFM, Qiangzhi decoction, curcumin, Shen-Fu, Forsythia, and Alpha-Mangostin inhibit the production of IL-6. Andrographolide and Liu Shen Wan have an inhibitory effect on releasing this agent, while Ilex Asprella and Deoxy-11,12-didehydroandrographolide and naringin reduce the expression of IL-6. Theaflavin and Cholorogenic acid inhibit the secretion of IL-6, Xuebijing, and Chai-Hu-Gui-Zi-Gan-Jiang-Tang and Lipanpaidu prescription can reduce the serum level of IL-6. These agents also effectively improve infected lungs, increase survival rates, and minimize tissue damage. Medicinal plants and their phytochemical ingredients with down-regulatory effects on the expression of IL-6 have a potential influence on the inhibition of cytokine storms during viral infection caused by COVID-19. Therefore, phytochemicals could be regarded as promising candidates for managing cytokine storm inflammatory responses due to COVID-19 infection.

Graphical AbstractInhibition of proteolytic and deubiquitinase activity of SARS-CoV-2 PLpro enzyme by phytochemicals.