scholarly journals Repositioning Therapeutics for COVID-19: Virtual Screening of the Potent Synthetic and Natural Compounds as SARS-CoV-2 3CLpro Inhibitors

2020 ◽  
Author(s):  
Ahmad Sattari ◽  
Ali Ramazani ◽  
Hamideh Aghahosseini
Keyword(s):  
Therapeutic Potential ◽  
Cost Effective ◽  
Natural Compounds ◽  
Drug Candidate ◽  
Docking Simulations ◽  
Global Challenge ◽  
Acyl Glucuronide ◽  
Approved Drugs ◽  
Kappa Carrageenan

Abstract Today, finding potential therapeutics for COVID-19 caused by the widespread transmission of SARS-CoV-2 has become a global challenge. Molecular docking investigation of the therapeutic potential of marketed drugs is a fast and cost effective approach to provide a solution to this problem. In this study, docking simulations performed on the reported structure of the virus main protease, 3CLpro, to identify potential inhibitors. Accordingly, a database of 50 synthetic compounds including approved drugs and those undergoing clinical trials, and 40 natural compounds particularly those employed in traditional Iranian medicine was constructed. The results indicated that the anti-inflammatory drugs, Licofelone acyl glucuronide and delta-bilirubin, and natural compounds such as kappa-carrageenan conformer and beta-D-galactopyranosyl with minimal side-effects, according to in-vitro studies, are good candidates to block the enzymatic activity of SARS-CoV-2 3CLpro. Moreover, the compound 1 could be a potential drug candidate for COVID-19 due to its favorable interactions with the 3CLpro.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

scholarly journals Complete biosynthetic pathways of ascofuranone and ascochlorin inAcremonium egyptiacum

2019 ◽  
Vol 116 (17) ◽  
pp. 8269-8274 ◽  
Author(s):  
Yasuko Araki ◽  
Takayoshi Awakawa ◽  
Motomichi Matsuzaki ◽  
Rihe Cho ◽  
Yudai Matsuda ◽  
...  
Keyword(s):  
Differential Expression Analysis ◽  
Cost Effective ◽  
Drug Candidate ◽  
P450 Monooxygenase ◽  
Genome Wide ◽  
Common Precursor ◽  
A Genome ◽  
Membrane Bound ◽  
The Cost

Ascofuranone (AF) and ascochlorin (AC) are meroterpenoids produced by various filamentous fungi, includingAcremonium egyptiacum(synonym:Acremonium sclerotigenum), and exhibit diverse physiological activities. In particular, AF is a promising drug candidate against African trypanosomiasis and a potential anticancer lead compound. These compounds are supposedly biosynthesized through farnesylation of orsellinic acid, but the details have not been established. In this study, we present all of the reactions and responsible genes for AF and AC biosyntheses inA. egyptiacum, identified by heterologous expression, in vitro reconstruction, and gene deletion experiments with the aid of a genome-wide differential expression analysis. Both pathways share the common precursor, ilicicolin A epoxide, which is processed by the membrane-bound terpene cyclase (TPC) AscF in AC biosynthesis. AF biosynthesis branches from the precursor by hydroxylation at C-16 by the P450 monooxygenase AscH, followed by cyclization by a membrane-bound TPC AscI. All genes required for AC biosynthesis (ascABCDEFG) and a transcriptional factor (ascR) form a functional gene cluster, whereas those involved in the late steps of AF biosynthesis (ascHIJ) are present in another distantly located cluster. AF is therefore a rare example of fungal secondary metabolites requiring multilocus biosynthetic clusters, which are likely to be controlled by the single regulator, AscR. Finally, we achieved the selective production of AF inA. egyptiacumby genetically blocking the AC biosynthetic pathway; further manipulation of the strain will lead to the cost-effective mass production required for the clinical use of AF.

scholarly journals Natural compounds attenuate heavy metal-induced PC12 cell damage

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052093084
Author(s):  
Lina Yang ◽  
Keshu Shen ◽  
Dongping Ji
Keyword(s):  
Heavy Metal ◽  
Pc12 Cells ◽  
Pc12 Cell ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Mitochondrial Protein ◽  
Natural Compounds ◽  
Alpha Tocopherol ◽  
Neuroprotective Effects

Objectives To investigate the neuroprotective effects of six natural compounds (caffeine, gallic acid, resveratrol, epigallocatechin gallate [EGCG], L-ascorbic acid and alpha tocopherol [Vitamin E] on heavy metal-induced cell damage in rat PC12 cells. Methods In this in vitro experiment, rat PC12 cells were exposed to four heavy metals (CdCl2, HgCl2, CoCl2 and PbCl2) at different concentrations and cell apoptosis, necrosis and oxidative stress were assessed with and without the addition of the six natural compounds. Results The metals decreased cell viability but the natural compounds attenuated their effects on apoptosis, necrosis and reactive oxygen species (ROS) levels. Mitochondrial protein changes were involved in the regulation. Conclusion Overall, the natural compounds did provide protection against the metal-induced PC12 cell damage. These data suggest that natural compounds may have therapeutic potential against metal-induced neurodegenerative disease.

Antiviral Potential of Spondias mombin L. Leaves Extract Against Herpes Simplex Virus Type-1 Replication Using In Vitro and In Silico Approaches

Planta Medica ◽  
2020 ◽  
Vol 86 (07) ◽  
pp. 505-515 ◽  
Author(s):  
Emerson M. da S. Siqueira ◽  
Tábata L. C. Lima ◽  
Laurita Boff ◽  
Sarah G. M. Lima ◽  
Estela M. G. Lourenço ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
Binding Mode ◽  
Surface Glycoprotein ◽  
Viral Attachment ◽  
Docking Simulations ◽  
Simplex Virus ◽  
Hsv 1

Abstract Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

scholarly journals A narrative review of herbal preparations against RNA viruses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Eghbal Jasemi ◽  
Saeideh Momtaz ◽  
Reza Ghaffarzadegan ◽  
Amir Hossein Abdolghaffari ◽  
Mohammad Abdollahi
Keyword(s):  
Infectious Diseases ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Synthetic Compound ◽  
Novel Approach ◽  
Plant Families ◽  
Approved Drugs ◽  
Almost All

Background: Throughout history, the plant kingdom has been a source of medicine in almost all cultures. Nowadays, ensuring the safety, quality, and effectiveness of medicinal herbs and their products has become an essential issue in industrialized and developing countries. Phytochemicals are usually involved in pharmacological actions and are used worldwide for various purposes, including the treatment of infectious diseases. Objectives: Although several therapeutics were designed to control infectious diseases, viral infections are still fatal. Currently, evidence extracted from in vivo, in vitro, and silico studies support the antiviral activity of many herbs scientifically; however, the therapeutic potential of many other herbs is still unknown. Plants and their products may potentially control the propagation of viruses in a variety of conditions. Methods: Data were extracted from PubMed, Scopus, Google Scholar, and Science Direct from 1983-2020. We gathered a list of plant extracts, phytochemicals, and herbal formulations that can inhibit RNA viral infections, mainly those are originated from the coronaviruses family. We also provided an overview of their inhibitory mechanism of actions. Results: Plant families, including Lamiaceae, Asteraceae, and Myrtaceae, contain the highest number of species with anti-coronaviruses activities, respectively. Conclusion: It can be suggested that the combination of these antiviral ingredients with each other, any synthetic compound, or already approved drugs or inhibitors can be a novel approach for antiviral therapies.  

scholarly journals Thrombin-derived C-terminal peptide reduces Candida -induced inflammation and infection in vitro and in vivo

2021 ◽  
Author(s):  
Anna Dahlman ◽  
Manoj Puthia ◽  
Jitka Petrlova ◽  
Artur Schmidtchen ◽  
Ganna Petruk
Keyword(s):  
Therapeutic Potential ◽  
Fluorescence Analysis ◽  
Viable Count ◽  
Drug Candidate ◽  
Dual Function ◽  
Reporter Mice ◽  
Transmission Electron ◽  
Novel Drug

Infections due to the opportunistic fungus Candida have been on the rise in the last decades, especially in immunocompromised individuals and hospital settings. Unfortunately, the treatments available today are limited. Thrombin-derived C-terminal peptide (TCP-25) is an antimicrobial peptide (AMP) with antibacterial and immunomodulatory effects. In this work, we, for the first time, demonstrate TCP-25’s ability to counteract Candida in vitro and in vivo . Using a combination of viable count assay, radial diffusion assay, fluorescence and transmission electron microscopy analyses, TCP-25 was found to exert a direct fungicidal activity. An inhibitory activity of TCP-25 on NF-κB activation induced by both zymosan alone and heat-killed C. albicans was demonstrated in vitro using THP-1 cells, and in vivo using NF-κB reporter mice. Moreover, the immunomodulatory property of TCP-25 was further substantiated in vitro by analyzing cytokine responses in human blood stimulated with zymosan, and in vivo employing a zymosan-induced peritonitis model in C57BL/6 mice. The therapeutic potential of TCP-25 was demonstrated in mice infected with luminescent C. albicans . Finally, the binding between TCP-25 and zymosan was investigated using circular dichroism spectroscopy and intrinsic fluorescence analysis. Taken together, our results show that TCP-25 has a dual function by inhibiting Candida as well as the associated zymosan-induced inflammation. The latter function is accompanied by a change in secondary structure upon binding to zymosan. TCP-25, therefore, shows promise as a novel drug candidate against Candida infections.

scholarly journals In vitro antimicrobial evaluation of toothpastes with natural compounds

2015 ◽  
Vol 09 (04) ◽  
pp. 580-586 ◽  
Author(s):  
Priscila de Camargo Smolarek ◽  
Luis Antonio Esmerino ◽  
Ana Cláudia Chibinski ◽  
Marcelo Carlos Bortoluzzi ◽  
Elizabete Brasil dos Santos ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
In Vitro Study ◽  
Study Groups ◽  
Natural Compounds ◽  
Antimicrobial Activities ◽  
Positive Control ◽  
Negative Control ◽  
Diffusion Method ◽  
Disk Diffusion Method

ABSTRACT Objectives: This in vitro study evaluated the antimicrobial effects of commercial toothpastes containing natural compounds. Materials and Methods: The study groups were divided based on the natural compound present in the toothpaste composition: Sorbitol (I), tocopherol (II), mint (III), cinnamon/mint (IV), propolis/melaleuca (V), mint/açai (VI), mint/guarana (VII), propolis (VIII), negative control (IX), and the positive control (X). The antimicrobial properties of the toothpastes were tested using the disk diffusion method against oral pathogens: Streptococcus mutans, Pseudomonas aeruginosa, and Enterococcus faecalis. The resulting inhibition halos were measured in millimeters. Results: The data indicated that the bacteria responded differently to the toothpastes (P < 0.0001). The diameters of the inhibition halos against S. mutans were in decreasing order of efficacy: Propolis/melaleuca > mint/guarana > mint/açai > sorbitol > tocopherol > cinnamon/mint > propolis > mint (P < 0.001 vs. negative control). E. faecalis showed variable responses to the dentifrices in the following order of decreasing efficacy: Mint/guarana > propolis > sorbitol > mint/açai > tocopherol > cinnamon/mint > mint = propolis/melaleuca = negative control. The product with the highest antimicrobial activity was mint/guarana, which was significantly different than propolis/melaleuca, mint, cinnamon/mint, and tocopherol and negative control (P < 0.001). The statistical analysis indicated that propolis, sorbitol, and mint/açai did not show any differences compared to mint/guarana (P > 0.05) and positive control (P > 0.05). P. aeruginosa was resistant to all dental gels tested including positive control. Conclusion: The toothpastes with natural compounds have therapeutic potential and need more detailed searches for the correct clinic therapeutic application. The results from this study revealed differences in the antimicrobial activities of commercial toothpastes with natural compounds.

scholarly journals Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4

2019 ◽  
Vol 20 (3) ◽  
pp. 530 ◽  
Author(s):  
Po-Kai Huang ◽  
Shian-Ren Lin ◽  
Jirawat Riyaphan ◽  
Yaw-Syan Fu ◽  
Ching-Feng Weng
Keyword(s):  
Single Dose ◽  
Natural Compounds ◽  
Dipeptidyl Peptidase ◽  
Antidiabetic Activity ◽  
Drug Candidate ◽  
Diabetic Patients ◽  
Dose Administration ◽  
Dipeptidyl Peptidase 4

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

scholarly journals Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-32 ◽  
Author(s):  
Marco Malavolta ◽  
Massimo Bracci ◽  
Lory Santarelli ◽  
Md Abu Sayeed ◽  
Elisa Pierpaoli ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Therapeutic Potential ◽  
Epigallocatechin Gallate ◽  
Natural Compounds ◽  
Related Factor ◽  
Phenethyl Isothiocyanate ◽  
Toxic Compounds ◽  
In Vivo Effects

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

scholarly journals Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 808
Author(s):  
Stefanie Deinhardt-Emmer ◽  
Laura Jäckel ◽  
Clio Häring ◽  
Sarah Böttcher ◽  
Janine J. Wilden ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Cost Effective ◽  
Multiple Organ ◽  
Drug Candidate ◽  
Phosphatidylinositol 3 Kinase ◽  
Virus Propagation ◽  
Pandemic Strains ◽  
Antiviral Medications ◽  
Phosphatidylinositol 3

Influenza virus (IV) infections are considered to cause severe diseases of the respiratory tract. Beyond mild symptoms, the infection can lead to respiratory distress syndrome and multiple organ failure. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. Interestingly, the virus-supportive function of the cellular phosphatidylinositol 3-kinase (PI3K) suggests that this signaling module may be a potential target for antiviral intervention. In the sense of repurposing existing drugs for new indications, we used Pictilisib, a known PI3K inhibitor to investigate its effect on IV infection, in mono-cell-culture studies as well as in a human chip model. Our results indicate that Pictilisib is a potent inhibitor of IV propagation already at early stages of infection. In a murine model of IV pneumonia, the in vitro key findings were verified, showing reduced viral titers as well as inflammatory response in the lung after delivery of Pictilisib. Our data identified Pictilisib as a promising drug candidate for anti-IV therapies that warrant further studying. These results further led to the conclusion that the repurposing of previously approved substances represents a cost-effective and efficient way for development of novel antiviral strategies.

Sign in / Sign up

Export Citation Format

Share Document