scholarly journals Elucidating design principles for engineering cell-derived vesicles to inhibit SARS-CoV-2 infection

2021 ◽  
Author(s):  
Taylor Franklin Gunnels ◽  
Devin M Stranford ◽  
Neha Kamat ◽  
Joshua Nathaniel Leonard
Keyword(s):  
Drug Resistance ◽  
Comparative Evaluation ◽  
Viral Infections ◽  
Repeated Administration ◽  
Binding Affinities ◽  
Impact Performance ◽  
Quantitative Understanding ◽  
Low Toxicity ◽  
Manufacturing Methods ◽  
Global Health Challenge

The ability of pathogens to develop drug resistance is a global health challenge. The SARS-CoV-2 virus presents an urgent need wherein several variants of concern resist neutralization by monoclonal antibody therapies and vaccine-induced sera. Decoy nanoparticles (cell-mimicking particles that bind and inhibit virions) are an emerging class of therapeutics that may overcome such drug resistance challenges. To date, we lack quantitative understanding as to how design features impact performance of these therapeutics. To address this gap, here we perform a systematic, comparative evaluation of various biologically-derived nanoscale vesicles, which may be particularly well-suited to sustained or repeated administration in the clinic due to low toxicity, and investigate their potential to inhibit multiple classes of model SARS-CoV-2 virions. A key finding is that such particles exhibit potent antiviral efficacy across multiple manufacturing methods, vesicle subclasses, and virus-decoy binding affinities. In addition, these cell-mimicking vesicles effectively inhibit model SARS-CoV-2 variants that evade monoclonal antibodies and recombinant protein-based decoy inhibitors. This study provides a foundation of knowledge that may guide the design of decoy nanoparticle inhibitors for SARS-CoV-2 and other viral infections.

Current insights into the chemistry and antitubercular potential of benzimidazole and imidazole derivatives

2020 ◽  
Vol 20 ◽  
Author(s):  
Deepa Parwani ◽  
Sushanta Bhattacharya ◽  
Akash Rathore ◽  
Chaitali Mallick ◽  
Vivek Asati ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multi Drug Resistance ◽  
Benzimidazole Derivatives ◽  
Duration Of Treatment ◽  
Structure Activity ◽  
Mdr Tb ◽  
Low Toxicity ◽  
Extensively Drug Resistance ◽  
Improved Characteristics

: Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure activity relationships in the treatment of tuberculosis.

scholarly journals Nanobiocide Based-Silver Nanomaterials Upon Coronaviruses: Approaches for Preventing Viral Infections

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kamyar Khoshnevisan ◽  
Hassan Maleki ◽  
Hadi Baharifar
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Agents ◽  
Long Term Stability ◽  
Silver Nanomaterials ◽  
Inhibitory Mechanisms ◽  
Low Toxicity ◽  
Nano Graphene

Abstract The effectiveness of silver nanomaterials (AgNMs), as antiviral agents, has been confirmed in humans against many different types of viruses. Nanobiocides-based AgNMs can be effectively applied to eliminate coronaviruses (CoVs), as the cause of various diseases in animals and humans, particularly the fatal human respiratory infections. Mostly, these NMs act effectively against CoVs, thanks to the NMs’ fundamental anti-viral structures like reactive oxygen species (ROS), and photo-dynamic and photo-thermal abilities. Particularly, the antiviral activity of AgNMs is clarified under three inhibitory mechanisms including viral entry limitation, attachment inhibition, and viral replication limitation. It is believed that nanobiocide with other possible materials such as TiO2, silica and, carbon NMs exclusively nano-graphene materials can emerge as a more effective disinfectant for long-term stability with low toxicity than common disinfectants. Nanobiocides also can be applied for the prevention and treatment of viral infections specifically against COVID-19. Graphic Abstract

scholarly journals Functionalized Chitosan Nanomaterials: A Jammer for Quorum Sensing

Polymers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 2533
Author(s):  
Moupriya Nag ◽  
Dibyajit Lahiri ◽  
Dipro Mukherjee ◽  
Ritwik Banerjee ◽  
Sayantani Garai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Quorum Sensing ◽  
Targeted Delivery ◽  
Direct Interaction ◽  
Orthodontic Appliances ◽  
Chronic Infections ◽  
Functionalized Nanomaterials ◽  
Low Toxicity ◽  
Novel Target ◽  
Positively Charged

The biggest challenge in the present-day healthcare scenario is the rapid emergence and spread of antimicrobial resistance due to the rampant use of antibiotics in daily therapeutics. Such drug resistance is associated with the enhancement of microbial virulence and the acquisition of the ability to evade the host’s immune response under the shelter of a biofilm. Quorum sensing (QS) is the mechanism by which the microbial colonies in a biofilm modulate and intercept communication without direct interaction. Hence, the eradication of biofilms through hindering this communication will lead to the successful management of drug resistance and may be a novel target for antimicrobial chemotherapy. Chitosan shows microbicidal activities by acting electrostatically with its positively charged amino groups, which interact with anionic moieties on microbial species, causing enhanced membrane permeability and eventual cell death. Therefore, nanoparticles (NPs) prepared with chitosan possess a positive surface charge and mucoadhesive properties that can adhere to microbial mucus membranes and release their drug load in a constant release manner. As the success in therapeutics depends on the targeted delivery of drugs, chitosan nanomaterial, which displays low toxicity, can be safely used for eradicating a biofilm through attenuating the quorum sensing (QS). Since the anti-biofilm potential of chitosan and its nano-derivatives are reported for various microorganisms, these can be used as attractive tools for combating chronic infections and for the preparation of functionalized nanomaterials for different medical devices, such as orthodontic appliances. This mini-review focuses on the mechanism of the downregulation of quorum sensing using functionalized chitosan nanomaterials and the future prospects of its applications.

scholarly journals Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

2020 ◽  
Author(s):  
Meenakshisundaram Balasubramaniam ◽  
Robert Shmookler Reis
Keyword(s):  
Small Molecules ◽  
Drug Targeting ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Hiv Treatment ◽  
Investigational Drug ◽  
Docking Simulations ◽  
Investigational Drugs ◽  
Low Toxicity

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.

scholarly journals Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

2020 ◽  
Author(s):  
Ozgun Kocabiyik ◽  
Valeria Cagno ◽  
Paulo Jacob Silva ◽  
Yong Zhu ◽  
Laura Sedano ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
New Class ◽  
Influenza Strain ◽  
Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

scholarly journals Identification of 1, 2, 4-triazine and its derivatives against Lanosterol 14 - demethylase (CYP51) property of Candida albicans: Influence on the development of new antifungal therapeutic strategies

2021 ◽  
Author(s):  
Abhishek Kumar Verma ◽  
Aarfah Majid ◽  
Md. Shahadat Hossain ◽  
Sk. Faisal Ahmed ◽  
Mohammad Ashid ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Molecular Docking ◽  
Hydrogen Bonds ◽  
Antifungal Drugs ◽  
Binding Affinities ◽  
Modern Drug ◽  
Low Toxicity ◽  
Derivatives Of ◽  
High Binding Affinity

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

scholarly journals Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-Like Protease Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4896
Author(s):  
Marjorie C. L. C. Freire ◽  
Gabriela D. Noske ◽  
Natália V. Bitencourt ◽  
Paulo R. S. Sanches ◽  
Norival A. Santos-Filho ◽  
...  
Keyword(s):  
Viral Infections ◽  
Binding Mode ◽  
Global Scale ◽  
New Drugs ◽  
Binding Affinities ◽  
Main Protease ◽  
Inhibitory Activities ◽  
Inhibition Potencies ◽  
Catalytic Cleft ◽  
Micromolar Range

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28–65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0–3.5 µM) and binding affinities (Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.

scholarly journals Evaluation of Toxicity, Bacteriostatic, Analgesic, Anti-Inflammatory, and Antipyretic Activities of Huangqin-Honghua-Pugongying-Jinyinhua Extract

2021 ◽  
Vol 8 (12) ◽  
pp. 330
Author(s):  
Dongyang Ye ◽  
Jing Sun ◽  
Yinqian Li
Keyword(s):  
Drug Resistance ◽  
Clinical Symptoms ◽  
Bovine Mastitis ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
Antipyretic Activity ◽  
Low Toxicity ◽  
Anti Inflammatory

The extensive use of antibiotics has caused the global spread of multidrug-resistant bacteria and genes, seriously reducing antibiotic efficacy and threatening animal and human health. As an alternative, traditional Chinese veterinary medicine (TCVM) was used in this study for its lack of drug resistance and low toxicity. Huangqin-honghua-pugongying-jinyinhua extract (HHPJE), a novel TCVM, consists of the extracts of Huangqin (Scutellaria baicalensis), Honghua (Carthami Flos), Pugongying (Taraxacum) and Jinyinhua (Lonicerae Japonicae Flos), and was developed to treat bovine mastitis. In this study, we evaluated the toxicity, bacteriostatic, analgesic, anti-inflammatory, and antipyretic activities of HHPJE. Our results show that HHPJE did not show any acute oral toxicity and can be considered safe for oral administration. Additionally, HHPJE possessed a dose-dependent antibacterial effect on Staphylococcus aureus, Escherichia coli, Streptococcus agalactiae and Streptococcus dysgalactiae. HHPJE (60, 30 and 15 g/kg) can reduce the abdominal pain by 44.83 ± 7.69%, 43.15 ± 9.50% and 26.14 ± 4.17%, respectively. The percentages of anti-inflammation inhibition (60, 30 and 15 g/kg) were 35.34 ± 2.17%, 22.29 ± 2.74% and 12.06 ± 3.61%, respectively. The inhibition rates (60, 30 and 15 g/kg) of antipyretic activity were 82.05%, 65.71% and 52.80%, respectively. The evaluation of pharmacodynamics and toxicity indicate that HHPJE possesses significant bacteriostatic, analgesic, anti-inflammatory and antipyretic potential, and also that it is safe for acute oral toxicity, which means it has potential value for treating bovine mastitis in future and alleviating clinical symptoms with no drug resistance or side effects.

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