scholarly journals Activation and Deactivation of a Broad-Spectrum Antiviral Drug by a Single Enzyme: Adenosine Deaminase Catalyzes Two Consecutive Deamination Reactions

2003 ◽  
Vol 47 (1) ◽  
pp. 426-431 ◽  
Author(s):  
Jim Zhen Wu ◽  
Heli Walker ◽  
Johnson Y. N. Lau ◽  
Zhi Hong
Keyword(s):  
Adenosine Deaminase ◽  
Broad Spectrum ◽  
Structural Information ◽  
Antiviral Drug ◽  
Therapeutic Index ◽  
Comprehensive Understanding ◽  
Liver Targeting ◽  
Inactive Metabolite ◽  
Single Enzyme

ABSTRACT Ribavirin is an approved broad-spectrum antiviral drug. A liver-targeting prodrug of ribavirin, viramidine, is in clinical trial in an attempt to provide a better therapeutic index. The conversion of viramidine to ribavirin, and of ribavirin to an inactive metabolite through adenosine deaminase, is reported. Kinetic analysis indicates that adenosine deaminase is likely involved in activation of viramidine in vivo, and the process is highly pH sensitive. The differential activities of two consecutive deamination reactions are kinetically studied and interpreted based on adenosine deaminase structural information. A comprehensive understanding of the viramidine and ribavirin deamination mechanism should help in designing better nucleoside therapeutics in the future.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Nanoparticles Enable Efficient Delivery of Antimicrobial Peptides for the Treatment of Deep Infections

2021 ◽  
Author(s):  
Yingxue Deng ◽  
Rui Huang ◽  
Songyin Huang ◽  
Menghua Xiong
Keyword(s):  
Antimicrobial Peptides ◽  
Broad Spectrum ◽  
Antimicrobial Properties ◽  
Therapeutic Index ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria ◽  
Efficient Delivery ◽  
Delivery Vehicles

Antimicrobial peptides (AMPs) have emerged as promising alternatives of traditional antibiotics against drug-resistant bacteria owing to their broad-spectrum antimicrobial properties and low tendency to drugresistance. However, their therapeutic efficacy in vivo, especially for infections in deep organs, is limited owing to their systemic toxicity and low bioavailability. Nanoparticles-based delivery systems offer a strategy to increase the therapeutic index of AMPs by preventing proteolysis, increasing the accumulation at infection sites, and reducing toxicity. Herein, we will discuss the current progress of using nanoparticles as delivery vehicles for AMPs for the treatment of deep infections.

scholarly journals Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

2020 ◽  
Author(s):  
Xi Yu ◽  
Liming Zhang ◽  
Liangqin Tong ◽  
Nana Zhang ◽  
Han Wang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Lipase Activity ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Viral Envelope ◽  
Global Public Health ◽  
Virucidal Activity ◽  
Extracellular Milieu

AbstractViruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

scholarly journals Flexibility and mobility of SARS-CoV-2-related protein structures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rudolf A. Römer ◽  
Navodya S. Römer ◽  
A. Katrine Wallis
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Large Scale ◽  
Structural Information ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Docking Studies ◽  
Related Protein

AbstractThe worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein—using its complete homo-trimer configuration with 2905 residues—our method identifies a large-scale opening and closing of the S1 subunit through movement of the S$${}^\text{B}$$ B domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.

scholarly journals Short Peptides Make a Big Difference: The Role of Botany-Derived AMPs in Disease Control and Protection of Human Health

2021 ◽  
Vol 22 (21) ◽  
pp. 11363
Author(s):  
Xiumei Luo ◽  
Wenxian Wu ◽  
Li Feng ◽  
Haim Treves ◽  
Maozhi Ren
Keyword(s):  
Antimicrobial Activity ◽  
Drug Design ◽  
Human Health ◽  
Broad Spectrum ◽  
Plant Protection ◽  
Antiviral Drug ◽  
Molecular Structures ◽  
Original Research ◽  
Pathogenesis Related Protein

Botany-derived antimicrobial peptides (BAMPs), a class of small, cysteine-rich peptides produced in plants, are an important component of the plant immune system. Both in vivo and in vitro experiments have demonstrated their powerful antimicrobial activity. Besides in plants, BAMPs have cross-kingdom applications in human health, with toxic and/or inhibitory effects against a variety of tumor cells and viruses. With their diverse molecular structures, broad-spectrum antimicrobial activity, multiple mechanisms of action, and low cytotoxicity, BAMPs provide ideal backbones for drug design, and are potential candidates for plant protection and disease treatment. Lots of original research has elucidated the properties and antimicrobial mechanisms of BAMPs, and characterized their surface receptors and in vivo targets in pathogens. In this paper, we review and introduce five kinds of representative BAMPs belonging to the pathogenesis-related protein family, dissect their antifungal, antiviral, and anticancer mechanisms, and forecast their prospects in agriculture and global human health. Through the deeper understanding of BAMPs, we provide novel insights for their applications in broad-spectrum and durable plant disease prevention and control, and an outlook on the use of BAMPs in anticancer and antiviral drug design.

Engineering of glycyrrhizin capped gold nanoparticles for liver targeting: in vitro evaluation and in vivo biodistribution study

RSC Advances ◽  
2016 ◽  
Vol 6 (51) ◽  
pp. 44944-44954 ◽  
Author(s):  
Shaivee Borker ◽  
Milind Patole ◽  
Alpana Moghe ◽  
Varsha Pokharkar
Keyword(s):  
Gold Nanoparticles ◽  
Antiviral Drug ◽  
Biodistribution Study ◽  
Liver Targeting ◽  
In Vitro Evaluation ◽  
In Vivo Biodistribution

Glycyrrhizin reduced and stabilized gold nanoparticles as carriers of antiviral drug lamivudine. The presence of glycyrrhizin enhanced uptake and localization of drug loaded gold nanoparticles in hepatocytes.

scholarly journals Using translational in vitro-in vivo modeling to improve drug repurposing outcomes for inhaled COVID-19 therapeutics

2021 ◽  
Author(s):  
Madison Stoddard ◽  
Lin Yuan ◽  
Arijit Chakravarty
Keyword(s):  
Antiviral Drug ◽  
Drug Repurposing ◽  
Therapeutic Index ◽  
Therapeutic Window ◽  
Stage Model ◽  
Validation Process ◽  
Specific Context ◽  
Model Driven

AbstractThe ongoing COVID-19 pandemic has created an urgent need for antiviral treatments that can be deployed rapidly. Drug repurposing represents a promising means of achieving this objective, but repurposing efforts are often unsuccessful. A common hurdle to effective drug repurposing is a failure to achieve a sufficient therapeutic window in the new indication. A clear example is the use of ivermectin in COVID-19, where the approved dose (administered orally) fails to achieve therapeutic concentrations in the lungs. Our proposed solution to the problem of ineffective drug repurposing for COVID-19 antivirals is two-fold: to broaden the therapeutic window by reformulating therapeutics for the pulmonary route, and to select drug repurposing candidates based on their model-predicted therapeutic index for inhalation. In this article, we propose a two-stage model-driven screening and validation process for selecting inhaled antiviral drug repurposing candidates. While we have applied this approach in the specific context of COVID-19, this in vitro-in vivo translational methodology is also broadly applicable to repurposing drugs for diseases of the lower respiratory tract.

scholarly journals Flexibility and mobility of SARS-CoV-2-related protein structures

2020 ◽  
Author(s):  
Rudolf A. Römer ◽  
Navodya S. Römer ◽  
A. Katrine Wallis
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Large Scale ◽  
Structural Information ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Docking Studies ◽  
Related Protein

ABSTRACTThe worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of SARS-CoV-2 drug targets, i.e. SARS-CoV-2 protein structures as deposited on the Protein Databank (PDB). We study their flexibility, rigidity and mobility, an important first step in trying to ascertain their dynamics for further drug-related docking studies. We are using a recent protein flexibility modelling approach, combining protein structural rigidity with possible motion consistent with chemical bonds and sterics. For example, for the SARS-CoV-2 spike protein in the open configuration, our method identifies a possible further opening and closing of the S1 subunit through movement of SB domain. With full structural information of this process available, docking studies with possible drug structures are then possible in silico. In our study, we present full results for the more than 200 thus far published SARS-CoV-2-related protein structures in the PDB.

scholarly journals A Novel Method to Predict Drug-Target Interactions Based on Large-Scale Graph Representation Learning

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2111
Author(s):  
Bo-Wei Zhao ◽  
Zhu-Hong You ◽  
Lun Hu ◽  
Zhen-Hao Guo ◽  
Lei Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
Large Scale ◽  
Computational Models ◽  
Structural Information ◽  
Characteristic Curve ◽  
Representation Learning ◽  
Graph Representation ◽  
Convolutional Network ◽  
Novel Method

Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a novel method called LGDTI to predict DTIs based on large-scale graph representation learning. LGDTI can capture the local and global structural information of the graph. Specifically, the first-order neighbor information of nodes can be aggregated by the graph convolutional network (GCN); on the other hand, the high-order neighbor information of nodes can be learned by the graph embedding method called DeepWalk. Finally, the two kinds of feature are fed into the random forest classifier to train and predict potential DTIs. The results show that our method obtained area under the receiver operating characteristic curve (AUROC) of 0.9455 and area under the precision-recall curve (AUPR) of 0.9491 under 5-fold cross-validation. Moreover, we compare the presented method with some existing state-of-the-art methods. These results imply that LGDTI can efficiently and robustly capture undiscovered DTIs. Moreover, the proposed model is expected to bring new inspiration and provide novel perspectives to relevant researchers.

scholarly journals Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 439
Author(s):  
Christopher G. Bunick ◽  
Jonette Keri ◽  
S. Ken Tanaka ◽  
Nika Furey ◽  
Giovanni Damiani ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Resistance ◽  
Antibiotic Use ◽  
In Vivo Studies ◽  
Infection Model ◽  
Severe Acne ◽  
Rat Paw Edema ◽  
Infection And Inflammation

Prolonged broad-spectrum antibiotic use is more likely to induce bacterial resistance and dysbiosis of skin and gut microflora. First and second-generation tetracycline-class antibiotics have similar broad-spectrum antibacterial activity. Targeted tetracycline-class antibiotics are needed to limit antimicrobial resistance and improve patient outcomes. Sarecycline is a narrow-spectrum, third-generation tetracycline-class antibiotic Food and Drug Administration (FDA)-approved for treating moderate-to-severe acne. In vitro studies demonstrated activity against clinically relevant Gram-positive bacteria but reduced activity against Gram-negative bacteria. Recent studies have provided insight into how the structure of sarecycline, with a unique C7 moiety, interacts with bacterial ribosomes to block translation and prevent antibiotic resistance. Sarecycline reduces Staphylococcus aureus DNA and protein synthesis with limited effects on RNA, lipid, and bacterial wall synthesis. In agreement with in vitro data, sarecycline demonstrated narrower-spectrum in vivo activity in murine models of infection, exhibiting activity against S. aureus, but reduced efficacy against Escherichia coli compared to doxycycline and minocycline. In a murine neutropenic thigh wound infection model, sarecycline was as effective as doxycycline against S. aureus. The anti-inflammatory activity of sarecycline was comparable to doxycycline and minocycline in a rat paw edema model. Here, we review the antibacterial mechanisms of sarecycline and report results of in vivo studies of infection and inflammation.

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