Identification of Therapeutically Active Molecules against Anthrax through Structure and Ligand based Drug Design

2019 ◽  
Vol 18 (27) ◽  
pp. 2294-2312
Author(s):  
Sisir Nandi ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Drug Design ◽  
Protective Antigen ◽  
Structural Features ◽  
Anthrax Toxin ◽  
Biological Warfare ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Pathogenic Viruses

Background: People suffer from fatal diseases which are responsible for mortality. Potent devices and medicines are being developed to fight diseases caused by the microorganism for saving the lives of individuals. Highly pathogenic viruses and bacteria are being incorporated into biological warfare, which has become a major threat to mankind and causes the destruction of lives in a short span of time. Objective: The pathogen Bacillus anthracis, which is the causative of anthrax, is used in bioterrorism. Efforts are therefore being made to study the progress of biodefense drug discovery research in combating anthrax-based bioterrorism. Methods: This review describes the present status of the studies ontherapeutic measurement of anthrax toxin inhibitors towards inhibition of protective antigen, lethal and edema factors using chemometric and drug design tools to explore essential structural features for further design of active congeneric compounds. Results: The inhibitors estimated to show high activity through different models may be proposed for further synthesis and testing of biological activity in terms of anthrax toxin inhibition and cytotoxicity testing by in vitro and in vivo assays. Conclusion: Such an attempt is an insight of biodefense drug design against the dreadful threat to the nation due to anthrax-based terrorism and biological warfare.

scholarly journals Detection of Anthrax Toxin in the Serum of Animals Infected with Bacillus anthracis by Using Engineered Immunoassays

2006 ◽  
Vol 13 (6) ◽  
pp. 671-677 ◽  
Author(s):  
Robert Mabry ◽  
Kathleen Brasky ◽  
Robert Geiger ◽  
Ricardo Carrion ◽  
Gene B. Hubbard ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Systemic Circulation ◽  
Rapid Identification ◽  
Anthrax Toxin ◽  
Soluble Form ◽  
Before And After

ABSTRACT Several strategies that target anthrax toxin are being developed as therapies for infection by Bacillus anthracis. Although the action of the tripartite anthrax toxin has been extensively studied in vitro, relatively little is known about the presence of toxins during an infection in vivo. We developed a series of sensitive sandwich enzyme-linked immunosorbent assays (ELISAs) for detection of both the protective antigen (PA) and lethal factor (LF) components of the anthrax exotoxin in serum. The assays utilize as capture agents an engineered high-affinity antibody to PA, a soluble form of the extracellular domain of the anthrax toxin receptor (ANTXR2/CMG2), or PA itself. Sandwich immunoassays were used to detect and quantify PA and LF in animals infected with the Ames or Vollum strains of anthrax spores. PA and LF were detected before and after signs of toxemia were observed, with increasing levels reported in the late stages of the infection. These results represent the detection of free PA and LF by ELISA in the systemic circulation of two animal models exposed to either of the two fully virulent strains of anthrax. Simple anthrax toxin detection ELISAs could prove useful in the evaluation of potential therapies and possibly as a clinical diagnostic to complement other strategies for the rapid identification of B. anthracis infection.

scholarly journals In Vitro and In Vivo Antitrypanosomal Activities of Methanol Extract of Echinops kebericho Roots

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Debela Abdeta ◽  
Nigatu Kebede ◽  
Mirutse Giday ◽  
Getachew Terefe ◽  
Solomon Mequanente Abay
Keyword(s):  
Body Weight ◽  
Neglected Tropical Diseases ◽  
Field Isolate ◽  
Parasite Load ◽  
Phytochemical Analysis ◽  
Isolation And Purification ◽  
Discovery Research ◽  
Drug Discovery Research

Microbial resistance to the few conventional antitrypanosomal drugs, increasing resistance of vectors to insecticides, lack of effective vaccines, and adverse effects of the existing antitrypanosomal drugs justify the urgent need for effective, tolerable, and affordable drugs. We assessed antitrypanosomal effects of the hydromethanolic extract of Echinops kebericho Mesfin roots against Trypanosoma congolense field isolate using in vitro and in vivo techniques. Parasite load, packed cell volume (PCV), body weight, and rectal temperature in Swiss albino mice were assessed. This finding is part of the outcomes of drug discovery research for neglected tropical diseases. The extract arrested the motility of trypanosomes within 40 min at 4 and 2 mg/mL concentration, whereas in the untreated control, motility continued for more than 160 min. The extract also reduced parasitemia and prevented drop in PCV and body weight significantly (p<0.05), as compared to control. Phytochemical analysis showed the presence of flavonoids, triterpenes, steroids, saponins, glycosides, tannins, and alkaloids. It is observed that this extract has activity against the parasite. Isolation and purification of specific compounds are required to identify hit compounds responsible for the antitrypanosomal activity of the studied medicinal plant.

scholarly journals Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

2013 ◽  
Vol 18 (10) ◽  
pp. 1234-1245 ◽  
Author(s):  
Ashley Wolfe ◽  
Belinda O’Clair ◽  
Vincent E. Groppi ◽  
Dyke P. McEwen
Keyword(s):  
Growth Factor ◽  
Umbilical Vein ◽  
Dermal Fibroblasts ◽  
Tube Length ◽  
Endothelial Cell Proliferation ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Angiogenesis Model

Angiogenesis, the formation of new vessels from preexisting vessels, involves multiple cell types acting in concert to cause endothelial cell proliferation, migration, and differentiation into microvascular arrays. Under pathologic conditions, microenvironment changes result in altered blood vessel production. Historically, in vitro angiogenesis assays study individual aspects of the process and tend to be variable, difficult to quantify, and limited in clinical relevance. Here, we describe a kinetic, quantitative, co-culture angiogenesis model and demonstrate its relevance to in vivo pharmacology. Similar to in vivo angiogenesis, a co-culture of human umbilical vein endothelial cells with normal human dermal fibroblasts remains sensitive to multiple cytokines, resulting in a concentration-dependent stimulation of tube formation over time. Treatment with axitinib, a selective vascular endothelial growth factor (VEGF) antagonist, inhibited VEGF-mediated tube length and branch point formation and was selective for inhibiting VEGF over basic fibroblast growth factor (bFGF), similar to previous studies. Conversely, an FGFR-1 selective compound, PD-161570, was more potent at inhibiting bFGF-mediated angiogenesis. These results demonstrate the cytokine dynamics, selective pharmacology, and translational application of this model system. Finally, combining quantitative angiogenic biology with kinetic, live-content imaging highlights the importance of using validated in vitro models in drug discovery research.

scholarly journals Anthrax Toxin-Mediated Delivery In Vivo and In Vitro of a Cytotoxic T-Lymphocyte Epitope from Ovalbumin

1998 ◽  
Vol 66 (2) ◽  
pp. 615-619 ◽  
Author(s):  
Jimmy D. Ballard ◽  
Amy M. Doling ◽  
Kathryn Beauregard ◽  
R. John Collier ◽  
Michael N. Starnbach
Keyword(s):  
Fusion Protein ◽  
T Lymphocyte ◽  
Self Assembly ◽  
Protective Antigen ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Lethal Factor ◽  
Anthrax Toxin

ABSTRACT We reported earlier that a nontoxic form of anthrax toxin was capable of delivering a cytotoxic T-lymphocyte (CTL) epitope in vivo, such that a specific CTL response was primed against the epitope. The epitope, of bacterial origin, was fused to an N-terminal fragment (LFn) from the lethal-factor component of the toxin, and the fusion protein was injected, together with the protective antigen (PA) component, into BALB/c mice. Here we report that PA plus LFn is capable of delivering a different epitope—OVA257–264 from ovalbumin. Delivery was accomplished in a different mouse haplotype,H-2Kb and occurred in vitro as well as in vivo. An OVA257–264-specific CTL clone, GA-4, recognized EL-4 cells treated in vitro with PA plus as little as 30 fmol of the LFn-OVA257–264 fusion protein. PA mutants attenuated in toxin self-assembly or translocation were inactive, implying that the role of PA in epitope delivery is the same as that in toxin action. Also, we showed that OVA257–264-specific CTL could be induced to proliferate by incubation with splenocytes treated with PA plus LFn-OVA257–264. These findings imply that PA-LFn may serve as a general delivery vehicle for CTL epitopes in vivo and as a safe, efficient tool for the ex vivo expansion of patient-derived CTL for use in adoptive immunotherapy.

Current Progress on the Genomics of Schistosomiasis for Drug Discovery and Diagnostics

2020 ◽  
Vol 20 (5) ◽  
pp. 598-610
Author(s):  
Nileshkumar Meghani ◽  
Beom-Jin Lee ◽  
Hardik Amin ◽  
Behzad Nili-Ahmadabadi ◽  
Saraswathy Nagendran
Keyword(s):  
Drug Discovery ◽  
Early Stage ◽  
Diagnostic Tools ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Tremendous Progress ◽  
Significant Research ◽  
Structural Insights

For a number of decades, schistosomiasis has remained a public threat and an economic burden in a number of countries, directly impacting over 200 million people. The past 15 years have seen tremendous progress in the development of high-throughput methods for targeting or compound selection that are vital to early-stage schistosome drug discovery research. Genomewide approaches to analyze gene expression at the transcriptional and other -omic levels have helped immensely for gaining insight into the pathways and mechanisms involved in the schistosomiasis and it is expected to revolutionize the drug discovery as well as related diagnostics. This review discusses the most recent progress of pharmacology and genomics concerning schistosomiasis with a focus on drug discovery and diagnostic tools. It also provides chemical structural insights of promising targets along with available in vitro and/or in vivo data. Although significant research has been done to identify new molecules for the treatment and new methods for diagnosis, the necessity of new options for the sustainable control of schistosomiasis remains a great challenge.

scholarly journals Preparation of Three-dimensional (3-D) Human Liver (HepaRG) Cultures for Histochemical and Immunohistochemical Staining and Light Microscopic Evaluation

2018 ◽  
Vol 46 (6) ◽  
pp. 653-659 ◽  
Author(s):  
Natasha P. Clayton ◽  
Alanna Burwell ◽  
Heather Jensen ◽  
Barbara F. Williams ◽  
Quashana D. Brown ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Human Liver ◽  
Three Dimensional ◽  
Culture Systems ◽  
Discovery Research ◽  
Glass Slides ◽  
Drug Discovery Research ◽  
Microscopic Evaluation

The use of three-dimensional (3-D) in vitro culture systems (spheroids, organoids) in biomolecular and drug discovery research has become increasingly popular. The popularity is due, in part, to a diminished reliance on animal bioassays and a desire to develop physiologically relevant cell culture systems that simulate the in vivo tissue microenvironment. Most evaluations of 3-D cultures are by confocal microscopy and high-content imaging; however, these technologies do not allow for detailed cellular morphologic assessments or permit basic hematoxylin and eosin histologic evaluations. There are few studies that have reported detailed processes for preparing 3-D cultures for paraffin embedding and subsequent use for histochemical or immunohistochemical staining. In an attempt to do so, we have developed a protocol to paraffin-embed human liver spheroids that can be sectioned with a microtome and mounted onto glass slides for routine histochemical and immunohistochemical staining and light microscopic evaluations.

scholarly journals Prophylaxis and Therapy of Inhalational Anthrax by a Novel Monoclonal Antibody to Protective Antigen That Mimics Vaccine-Induced Immunity

2006 ◽  
Vol 74 (10) ◽  
pp. 5840-5847 ◽  
Author(s):  
Laura Vitale ◽  
Diann Blanset ◽  
Israel Lowy ◽  
Thomas O'Neill ◽  
Joel Goldstein ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Antigen ◽  
Fc Receptor ◽  
Anthrax Toxin ◽  
Functional Assay ◽  
Human Mabs ◽  
Anthrax Spores ◽  
Anthrax Vaccines

ABSTRACT The neutralizing antibody response to the protective antigen (PA) component of anthrax toxin elicited by approved anthrax vaccines is an accepted correlate for vaccine-mediated protection against anthrax. We reasoned that a human anti-PA monoclonal antibody (MAb) selected on the basis of superior toxin neutralization activity might provide potent protection against anthrax. The fully human MAb (also referred to as MDX-1303 or Valortim) was chosen from a large panel of anti-PA human MAbs generated using transgenic mice immunized with recombinant PA solely on the basis of in vitro anthrax toxin neutralization. This MAb was effective in prophylactic and postsymptomatic treatment of rabbits exposed to aerosolized anthrax spores, and a single intramuscular injection of 1 mg/kg of body weight fully protected cynomolgus monkeys challenged with aerosolized anthrax spores. Importantly, MAb 1303 defines a novel neutralizing epitope that requires Fc receptor engagement for maximal activity. F(ab′)2 fragments of MAb 1303, which retain equivalent affinity for PA, are 10- to 100-fold less potent in neutralizing anthrax toxin in vitro. Addition of Fc receptor-blocking antibodies also greatly reduced the activity of MAb 1303. Moreover, we found that the neutralizing activity of mouse, rabbit, and human antisera elicited by PA vaccines was effectively abrogated by blocking Fc receptors. Selection of an anti-PA MAb by using a functional assay that is a surrogate for protection has resulted in the identification of a fully human MAb with potent activity in vivo and uncovered a previously unrecognized mechanism of antibody-mediated toxin neutralization that is important for currently used anthrax vaccines.

scholarly journals Chemical toxicity prediction based on semi-supervised learning and graph convolutional neural network

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jiarui Chen ◽  
Yain-Whar Si ◽  
Chon-Wai Un ◽  
Shirley W. I. Siu
Keyword(s):  
Neural Network ◽  
Supervised Learning ◽  
Superior Performance ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Toxicity Prediction ◽  
Discovery Research ◽  
Drug Discovery Research

AbstractAs safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases. Our optimal model SSL-GCN is hosted on an online server accessible through: https://app.cbbio.online/ssl-gcn/home.

Deletion mutants of protective antigen that inhibit anthrax toxin both in vitro and in vivo

2003 ◽  
Vol 307 (3) ◽  
pp. 446-450 ◽  
Author(s):  
Nidhi Ahuja ◽  
Praveen Kumar ◽  
Sheeba Alam ◽  
Megha Gupta ◽  
Rakesh Bhatnagar
Keyword(s):  
Protective Antigen ◽  
Anthrax Toxin ◽  
Deletion Mutants

scholarly journals Chemical Toxicity Prediction Based on Semi-supervised Learning and Graph Convolutional Neural Network

2021 ◽  
Author(s):  
Jiarui Chen ◽  
Yain-Whar Si ◽  
Chon-Wai Un ◽  
Shirley W. I. Siu
Keyword(s):  
Neural Network ◽  
Supervised Learning ◽  
Superior Performance ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Toxicity Prediction ◽  
Discovery Research ◽  
Drug Discovery Research

Abstract As safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases.

Sign in / Sign up

Export Citation Format

Share Document