scholarly journals Solution Structures and Dynamic Assembly of the 24-Meric Plasmodial Pdx1–Pdx2 Complex

2020 ◽  
Vol 21 (17) ◽  
pp. 5971
Author(s):  
Najeeb Ullah ◽  
Hina Andaleeb ◽  
Celestin Nzanzu Mudogo ◽  
Sven Falke ◽  
Christian Betzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Pyridoxal Phosphate ◽  
Plasmodium Species ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Enzyme Complex ◽  
Solution Structures ◽  
Dynamic Assembly ◽  
Bioanalytical Techniques ◽  
Initial Drug

Plasmodium species are protozoan parasites causing the deadly malaria disease. They have developed effective resistance mechanisms against most antimalarial medication, causing an urgent need to identify new antimalarial drug targets. Ideally, new drugs would be generated to specifically target the parasite with minimal or no toxicity to humans, requiring these drug targets to be distinctly different from the host’s metabolic processes or even absent in the host. In this context, the essential presence of vitamin B6 biosynthesis enzymes in Plasmodium, the pyridoxal phosphate (PLP) biosynthesis enzyme complex, and its absence in humans is recognized as a potential drug target. To characterize the PLP enzyme complex in terms of initial drug discovery investigations, we performed structural analysis of the Plasmodium vivax PLP synthase domain (Pdx1), glutaminase domain (Pdx2), and Pdx1–Pdx2 (Pdx) complex (PLP synthase complex) by utilizing complementary bioanalytical techniques, such as dynamic light scattering (DLS), X-ray solution scattering (SAXS), and electron microscopy (EM). Our investigations revealed a dodecameric Pdx1 and a monodispersed Pdx complex. Pdx2 was identified in monomeric and in different oligomeric states in solution. Interestingly, mixing oligomeric and polydisperse Pdx2 with dodecameric monodisperse Pdx1 resulted in a monodispersed Pdx complex. SAXS measurements revealed the low-resolution dodecameric structure of Pdx1, different oligomeric structures for Pdx2, and a ring-shaped dodecameric Pdx1 decorated with Pdx2, forming a heteromeric 24-meric Pdx complex.

Structure, function and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets

2007 ◽  
Vol 35 (5) ◽  
pp. 1325-1328 ◽  
Author(s):  
L.J. Alderwick ◽  
H.L. Birch ◽  
A.K. Mishra ◽  
L. Eggeling ◽  
G.S. Besra
Keyword(s):  
Cell Wall ◽  
Drug Targets ◽  
Infectious Agent ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
New Era ◽  
New Drug ◽  
Site Of Action ◽  
Wall Components

In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB, currently the leading cause of death from a single infectious agent, killing more than three million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host–pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV PG (peptidoglycan) to which is attached the macromolecular structure, mycolyl-arabinogalactan, via a unique diglycosylphosphoryl bridge. This review will discuss the assembly of the mAGP (mycolyl-arabinogalactan-peptidoglycan), its associated glycolipids and the site of action of EMB (ethambutol), bringing forward a new era in TB research and focus on new drugs to combat multidrug resistant TB.

scholarly journals High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes

Parasitology ◽  
2013 ◽  
Vol 141 (1) ◽  
pp. 77-82 ◽  
Author(s):  
DAVID HORN
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Drug Targets ◽  
Sequence Data ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Uptake ◽  
Microbial Pathogens ◽  
African Trypanosomes ◽  
Genome Scale

SUMMARYThe availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs.

Tuberculosis: a balanced diet of lipids and carbohydrates

2008 ◽  
Vol 36 (4) ◽  
pp. 555-565 ◽  
Author(s):  
Veemal Bhowruth ◽  
Luke J. Alderwick ◽  
Alistair K. Brown ◽  
Apoorva Bhatt ◽  
Gurdyal S. Besra
Keyword(s):  
Drug Targets ◽  
Infectious Agent ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Macromolecular Structure ◽  
New Era ◽  
Balanced Diet ◽  
Site Of Action ◽  
Wall Components

In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB currently the leading cause of death from a single infectious agent, killing more than 3 million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host–pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV peptidoglycan to which is attached the macromolecular structure, mycolyl-arabinogalactan via a unique diglycosylphosphoryl bridge. The present review discusses the assembly of the mAGP (mycolyl-arabinogalactan–peptidoglycan) complex and the site of action of EMB (ethambutol), bringing forward a new era in TB research and focus for new drugs to combat multidrug-resistant TB.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

scholarly journals A Multi-Pronged Computational Pipeline for Prioritizing Drug Target Strategies for Latent Tuberculosis

2020 ◽  
Vol 8 ◽  
Author(s):  
Ushashi Banerjee ◽  
Santhosh Sankar ◽  
Amit Singh ◽  
Nagasuma Chandra
Keyword(s):  
Drug Targets ◽  
Metabolic Flux ◽  
Latent Tuberculosis ◽  
Interaction Network ◽  
New Drugs ◽  
Prolonged Treatment ◽  
Flux Analysis ◽  
Protein Protein Interaction ◽  
Candidate Drug ◽  
Global Population

Tuberculosis is one of the deadliest infectious diseases worldwide and the prevalence of latent tuberculosis acts as a huge roadblock in the global effort to eradicate tuberculosis. Most of the currently available anti-tubercular drugs act against the actively replicating form of Mycobacterium tuberculosis (Mtb), and are not effective against the non-replicating dormant form present in latent tuberculosis. With about 30% of the global population harboring latent tuberculosis and the requirement for prolonged treatment duration with the available drugs in such cases, the rate of adherence and successful completion of therapy is low. This necessitates the discovery of new drugs effective against latent tuberculosis. In this work, we have employed a combination of bioinformatics and chemoinformatics approaches to identify potential targets and lead candidates against latent tuberculosis. Our pipeline adopts transcriptome-integrated metabolic flux analysis combined with an analysis of a transcriptome-integrated protein-protein interaction network to identify perturbations in dormant Mtb which leads to a shortlist of 6 potential drug targets. We perform a further selection of the candidate targets and identify potential leads for 3 targets using a range of bioinformatics methods including structural modeling, binding site association and ligand fingerprint similarities. Put together, we identify potential new strategies for targeting latent tuberculosis, new candidate drug targets as well as important lead clues for drug design.

scholarly journals Thiourea and Guanidine Compounds and their Iridium Complexes in Drug-Resistant Cancer Cell Lines: Structure-Activity Relationships and Direct Luminescent Imaging

2019 ◽  
Author(s):  
Samuel J. Thomas ◽  
Barbora Balonova ◽  
Jindrich Cinatl ◽  
Mark Wass ◽  
Christopher Serpell ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Nature Medicine ◽  
Cancer Cell Lines ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Iridium Complexes ◽  
Safety Issues ◽  
Structure Activity Relationships ◽  
Structure Activity

<p>Thiourea and guanidine units are found in nature, medicine, and materials. Their continued exploration in applications as diverse as cancer therapy, sensors, and electronics means that their toxicity is an important consideration. We have systematically synthesised a set of thiourea compounds and their guanidine analogues, and elucidated structure-activity relationships in terms of cellular toxicity in three ovarian cancer cell lines and their cisplatin-resistant sub-lines. We have been able to use the intrinsic luminescence of iridium complexes to visualise the effect of both structure alteration and cellular resistance mechanisms. These findings provide starting points for the development of new drugs and consideration of safety issues for novel thiourea- and guanidine-based materials.</p>

scholarly journals IN SILICO ANTIMALARIAL TARGET SELECTION CONSERVED IN FOUR PLASMODIUM SPECIES

2020 ◽  
Author(s):  
Oladoja AWofisayo
Keyword(s):  
Comparative Genomics ◽  
Peer Review ◽  
In Silico ◽  
Drug Targets ◽  
Homo Sapiens ◽  
Mammalian Species ◽  
Target Selection ◽  
Plasmodium Species ◽  
Data Bank ◽  
Sequence Motifs

Objectives: The need for new antimalarials drugs and drug targets is pertinent due to the emergence of drug resistant strains of the parasites. Improper target selection has resulted in therapeutic failure. The genomic/post genomic era has made possible the deciphering of the 3D crystal structures of proteins and DNA which are drug targets and are deposited in the protein data bank. Methods: Novel antimalarial targets obtained from evolutionary conserved short sequence motifs are utilised and are essential in transcription processes in the parasite. The motifs TGCATGCA, GTGCAC and GTGCGTGC were curated from experimental work, validated and analysed via phylogenomics genomics and comparative genomics. PlasmoDB blastn was applied to determine their similarity in Plasmodium vivax, knowlesi, Ovale and yoeli. The complete genome of Plasmodium falciparum vivax, knowlesi, Ovale and yoeli was downloaded from the plasmoDB and their positions determined. Results: The targets are essential, conserved in rodent and mammalian species via phylogenomics with percentage identity and similarity greater than 80%, have no similar genes in the same genome and also found to be selective in the parasites vis-à-vis the Homo sapiens via comparative genomics with 0% identity and similarity in the human genome. Conclusion: The targets reveal at the molecular and biochemical level, the vulnerable regions in the parasite while safe in human hence their choices in subsequent rationale drug discovery and design protocols. Peer Review History: Received: 18 July 2020; Revised: 1 October; Accepted: 12 October, Available online: 15 November 2020 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Dr. Tamer ELHABIBI, ERU University, Egypt, [email protected] Dr. Soroush Sardari, Biotech Pasteur Institute of Iran, Tehran, Iran, [email protected] Comments of reviewer(s): Similar Articles: IN SILICO LIGAND-BASED 2D PHARMACOPHORE GENERATION FOR H+/K+ ATPASE INHIBITORS

scholarly journals Global Proteomic Analysis of Listeria monocytogenes’ Response to Linalool

Foods ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2449
Author(s):  
Zhipeng Gao ◽  
Weiming Zhong ◽  
Ting Liu ◽  
Tianyu Zhao ◽  
Jiajing Guo
Keyword(s):  
Listeria Monocytogenes ◽  
Foodborne Pathogens ◽  
Proteomic Analysis ◽  
Drug Targets ◽  
Enrichment Analysis ◽  
Good Evidence ◽  
New Drugs ◽  
Organic System ◽  
Flow Cytometry Data ◽  
Theoretical Support

Listeria monocytogenes (LM) is one of the most serious foodborne pathogens. Listeriosis, the disease caused by LM infection, has drawn attention worldwide because of its high hospitalization and mortality rates. Linalool is a vital constituent found in many essential oils; our previous studies have proved that linalool exhibits strong anti-Listeria activity. In this study, iTRAQ-based quantitative proteomics analysis was performed to explore the response of LM exposed to linalool, and to unravel the mode of action and drug targets of linalool against LM. A total of 445 differentially expressed proteins (DEPs) were screened out, including 211 up-regulated and 234 down-regulated proteins which participated in different biological functions and pathways. Thirty-one significantly enriched gene ontology (GO) functional categories were obtained, including 12 categories in “Biological Process”, 10 categories in “Cell Component”, and 9 categories in “Molecular Function”. Sixty significantly enriched biological pathways were classified, including 6 pathways in “Cell Process”, 6 pathways in “Environmental Information Processing”, 3 pathways in “Human Disease”, 40 pathways in “Metabolism”, and 2 pathways in “Organic System”. GO and Kyoto Encyclopedia of Genes (KEGG) enrichment analysis together with flow cytometry data implied that cell membranes, cell walls, nucleoids, and ribosomes might be the targets of linalool against LM. Our study provides good evidence for the proteomic analysis of bacteria, especially LM, exposed to antibacterial agents. Further, those drug targets discovered by proteomic analysis can provide theoretical support for the development of new drugs against LM.

Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets

2003 ◽  
Vol 2 (4) ◽  
pp. 278-288 ◽  
Author(s):  
Donald M. Coen ◽  
Priscilla A. Schaffer
Keyword(s):  
Drug Targets ◽  
New Drugs

Multicenter Analysis of Genomically Targeted Single Patient Use Requests for Pediatric Neoplasms

2021 ◽  
Author(s):  
Himalee S. Sabnis ◽  
David S. Shulman ◽  
Benjamin Mizukawa ◽  
Nancy Bouvier ◽  
Ahmet Zehir ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Drug Administration ◽  
Pediatric Cancer ◽  
Drug Targets ◽  
De Novo ◽  
Food And Drug Administration ◽  
Hematologic Malignancies ◽  
New Drugs ◽  
Single Patient ◽  
Patient Use

PURPOSE The US Food and Drug Administration–expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

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