Therapeutic potential of green tea catechin, (-)-epigallocatechin-3-O-gallate (EGCG) in SARS-CoV-2 infection: Major interactions with host/virus proteases.

Background: The current COVID-19 pandemic from the human pathogenic virus SARS-CoV-2 has resulted in a major health hazard globally. The morbidity and transmission modality of this disease are severe and uncontrollable. As no effective clinical drugs are available for treatment of COVID-19 infection till to date and only vaccination is used as prophylaxis and its efficacy is restricted due to emergent of new variants of SARS-CoV-2, there is an urgent need for effective drugs for its treatment. Purpose: The aim of this review was to provide a detailed analysis of anti-SARS-CoV-2 efficacy of (-)-epigallocatechin-3-O-gallate (EGCG), a major catechin constituent of green tea (Camellia sinensis (L.) Kuntze) beverage to highlight the scope of EGCG in clinical medicine as both prophylaxis and treatment of present COVID-19 infection. In addition, the factors related to poor oral bioavailabilty of EGCG was also analysed for a suggestion for future research in this direction. Study design: We collected the published articles related to anti-SARS-CoV-2 activity of EGCG against the original strain (Wuhan type) and its newly emerged variants of SARS-CoV-2 virus. Methods: A systematic search on the published literature was conducted in various databases including Google Scholar, PubMed, Science Direct and Scopus to collect the relevant literature. Results: The findings of this search demonstrate that EGCG shows potent antiviral activity against SARS-CoV-2 virus by preventing viral entry and replication in host cells in vitro models. The studies on the molecular mechanisms of EGCG in inhibition of SARS-CoV-2 infection in host cells reveal that EGCG blocks the entry of the virus particles by interaction with the receptor binding domain (RBD) of viral spike (S) protein to host cell surface receptor protease angiotensin-converting enzyme 2 (ACE2) as well as suppression of the expressions of host proteases, ACE2, TMPRSS2 and GRP78, required for viral entry, by Nrf2 activation in host cells. Moreover, EGCG inhibits the activities of SARS-CoV-2 main protease (Mpro), papain-like protease (PLpro), endoribonuclease Nsp15 in vitro models and of RNA-dependent RNA polymerase (RdRp) in molecular docking model for suppression of viral replication. In addition, EGCG significantly inhibits viral inflammatory cytokine production by stimulating Nrf2- dependent host immune response in virus-infected cells. EGCG significantly reduces the elevated levels of HMGB1, a biomarker of sepsis, lung fibrosis and thrombotic complications in viral infections. EGCG potentially inhibits the infection of original (Wuhan type) strain of SARS-CoV-2 and other newly emerged variants as well as the infections of SARS-CoV-2 virus spike-protein of WT and its mutants-mediated pseudotyped viruses . EGCG shows maximum inhibitory effect against SARS-CoV-2 infection when the host cells are pre-incubated with the drug prior to viral infection. A sorbitol/lecithin-based throat spray containing concentrated green tea extract rich in EGCG content significantly reduces SARS-CoV-2 infectivity in oral mucosa. Several factors including degradation in gastrointestinal environment, low absorption in small intestine and extensive metabolism of EGCG are responsible for its poor bioavailability in humans. Pharmacokinetic and metabolism studies of EGCG in humans reveal poor bioavailability of EGCG in human plasma and EGCG-4"-sulfate is its major metabolite. The concentration of EGCG-4"-sulfate in human plasma is almost equivalent to that of free EGCG (Cmax 177.9 vs 233.5 nmol/L). These findings suggest that inhibition of sulfation of EGCG is a crucial factor for improvement of its bioavailability. In vitro study on the mechanism of EGCG sulfonation indicates that sulfotransferases, SULT1A1 and SULT1A3 are responsible for sulfonation in human liver and small intestine, respectively. Some attempts including structural modifications, and nanoformulations of EGCG and addition of nutrients with EGCG have been made to improve the bioavailability of EGCG. Conclusions: The findings of this study suggest that EGCG has strong antiviral activity against SARS-CoV-2 infection independent of viral strains (Wuhan type (WT), other variants) by inhibition of viral entry and replication in host cells in vitro models. EGCG may be useful in reduction of this viral load in salivary glands of COVID-19 patients, if it is applied in mouth and throat wash formulations in optimal concentrations. EGCG could be a promising candidate in the development of effective vaccine for prevention of the infections of newly emergent strains of SARS-CoV-2 virus. EGCG might be useful also as a clinical medicine for treatment of COVID-19 patients if its bioavailability in human plasma is enhanced.

TRP ion channels and approaches in COVID-19

Living systems have hundreds of ion channels on their surfaces. The TRP protein family defined in Drosophila is one of the channels providing ion passage and is present in living systems from simple organisms to complex. TRP channels have various roles in sensory systems and are located in almost all cells. TRP cation channels of mammals consist of seven subfamilies and each of them has their own structure, location etc. (Clapham, 2003). Since they play a role in sensory transmission, sciencists think that they could be potential targets for relieving the symptoms of various diseases (Miller, 2006). COVID-19 disease caused by the SARS-Cov-2 virus occurs with symptoms such as headache, muscle pain, respiratory and digestive problems, and loss of taste and smell. TRP channels have been targeted in some approaches to reduce these symptoms. In some studies that blocked TRP channels, the symptoms were observed to disappear or to decrease significantly (Fernandes et al., 2012). The virus requires angiotensin converting enzyme 2 and transmembrane protease serine 2 proteins to enter host cells. These processes are mediated by endocytosis and by Ca+ flow. In this context, it has been observed that the blocking of TRP channels hinders the entry of the virus into the host. The aim of this review is to examine the severe symptoms, the potential roles of TRP ion channels in the spread and progression processes of the COVID-19 pandemic, which led to a worldwide crisis, as well as their therapeutic approaches.

The Role of E3 Ligase Pirh2 in Disease.

The p53-dependent ubiquitin ligase Pirh2 regulates a number of proteins involved in different cancer-associated processes. Targeting the p53 family proteins, Chk2, p27Kip1, Twist1 and others, Pirh2 participates in such cellular processes as proliferation, cell cycle regulation, apoptosis and cellular migration. Thus, it is not surprising that Pirh2 takes part in the initiation and progression of different diseases and pathologies including but not limited to cancer. In this review, we aimed to summarize the available data on Pirh2 regulation, its protein targets and its role in various diseases and pathological processes, thus making the Pirh2 protein a promising therapeutic target.

Research advances and prospects of legume lectins

Lectins are widely distributed proteins having ability of binding selectively and reversibly with carbohydrates moieties and glycoconjugates. Although lectins have been reported from different biological sources, the legume lectins are the best-characterized family of plant lectins. Legume lectins are a large family of homologous proteins with considerable similarity in amino acid sequence and their tertiary structures. Despite having strong sequence conservation, these lectins show remarkable variability in carbohydrate specificity and quaternary structures. The ability of legume lectins in recognizing glycans and glycoconjugates on cells and other intracellular structures make them a valuable research tool in glycomic research. Due to variability in binding with glycans, glycoconjugates and multiple biological functions, legume lectins are the subject of intense research for their diverse application in different fields such as glycobiology, biomedical research and crop improvement. The present review specially focuses on structural and functional characteristics of legume lectins along with their potential areas of application.

Sequence similarity in 3D for comparison of protein families.

Homologous proteins are often compared by pairwise sequence alignment, and structure superposition if the atomic coordinates are available. Unification of sequence and structure data is an important task in structural biology. Here, we present the Sequence Similarity 3D (SS3D) method of integrating sequence and structure information. SS3D is a distance and substitution matrix-based method for straightforward visualization of regions of similarity and difference between homologous proteins. This work details the SS3D approach, and demonstrates its utility through case studies comparing members of several protein families. The examples show that SS3D can effectively highlight biologically important regions of similarity and dissimilarity. We anticipate that the method will be useful for numerous structural biology applications, including, but not limited to, studies of binding specificity, structure-function relationships, and evolutionary pathways. SS3D is available with a manual and tutorial at https://github.com/0x462e41/SS3D/.