Download or read book Plasmodium Falciparum Histone Deacetylases as Novel Antimalarial Drug Targets written by Thanh Nguyen Tran and published by . This book was released on 2010 with total page 278 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Inhibition of the Histone Deacetylase Family as a Drug Target in the Human Malaria Parasite Plasmodium Falciparum written by Nabila Ismail and published by . This book was released on 2014 with total page 208 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Drug Targets for Plasmodium Falciparum Historic to Future Perspectives written by Mohammed Tarique and published by Springer Nature. This book was released on with total page 205 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Drug Development for Malaria written by Pravin Kendrekar and published by John Wiley & Sons. This book was released on 2022-08-09 with total page 404 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drug Development for Malaria Provides readers with first-hand advice for the development of novel antimalarial drugs This book provides a systematic overview of antimalarial drug development and presents a wealth of data and insight from drug developers across three continents, including many from countries where the disease is endemic. Throughout, the contributions have been written with the drug developer in mind, highlighting challenges but also opportunities for the successful development of effective antimalarial drugs. Case studies and method-oriented chapters provide an abundance of practical first-hand advice on how to successfully develop an antimalarial drug. Key topics covered in the book include: The performance of current drugs and therapies, the influence of formulation and targeted delivery, and strategies to overcome drug resistance. Technologies and approaches for development of novel drugs, such as assays, computer-aided drug design, known and potential drug targets, and natural sources for novel antimalarial compounds Vaccination as an alternative to drug therapy For chemists and other professionals working in industries related to medicine and pharmaceuticals, this book provides a completely comprehensive overview of the current state of novel antimalarial drugs and how they can be developed in an efficient and cost-effective manner.
Download or read book Characterization and Analysis of Novel Antimalarial Drug Targets Plasmodium Falciparum Phosphatidylinositol Kinases written by Anna Rose Sternberg and published by . This book was released on 2020 with total page 372 pages. Available in PDF, EPUB and Kindle. Book excerpt: Artemisinin-based combination therapy (ACT) is the first-line treatment recommended for uncomplicated Plasmodium falciparum infections by the World Health Organization (WHO). ACTs are composed of an artemisinin (ART) drug and a longer lasting partner drug, typically with a mechanism of action (MOA) different from ARTs. With the exception of ARTs, there is widespread resistance to all antimalarial drug classes previously recommended for use against P. falciparum. However, the appearance of delayed clearance phenotype (DCP) infections due to reduced ACT efficacy in Southeast Asia [Noedl et al., 2008] threatens our ability to successfully treat multi-drug resistant P. falciparum malaria with ACTs. This also indicates the era of ARTs as leading antimalarial drugs may be reaching an end, so there is desperate need for the development of novel and potent antimalarials for use in next generation therapies.
Download or read book Assessment of the Drug Activity of Anti infectives Against Plasmodium Falciparum and Schistosoma Mansoni written by Erik Johannes Koehne and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Parasitic diseases continue to be a leading cause of disability, morbidity, and mortality in tropical and subtropical regions of the world. Malaria, an acute and life-threatening disease, causing significant mortality, and schistosomiasis, a predominantly chronic disease leading to long-term morbidity, are often found together in the same geographical area, principally affecting people of low socioeconomic status. Artemisinin-based combination therapies are currently recommended by WHO for the treatment of patients with uncomplicated malaria. Recent reports from Southeast Asia show a delay in the clearance of malaria parasites from the bloodstream after treatment with artemisinin- based combination therapies. Thus, raising concerns that the parasites may spread from Southeast Asia to sub-Saharan Africa or occur de novo. Moreover, praziquantel is the only available drug for the treatment of schistosomiasis. However, this monotherapy presents with several challenges including that it is not active against juvenile worms and the cure rate is rarely 100%. A drug or drug combinations targeting the adult and prepatent life cycle stages of schistosomes would be more effective in treating patients and would significantly reduce pathogen transmission rates. The aim of this study was to assess the activity of compounds targeting organelles of prokaryotic descent, epigenetic regulators, and the hemozoin synthesis pathway in Plasmodium and Schistosoma parasites. The first study evaluated antibiotics for their drug activity against P. falciparum and S. mansoni. The novel synthetic halogenated tetracycline derivative eravacycline, together with tetracycline, tigecycline, doxycycline, and the lincosamide clindamycin, were evaluated for their drug activity against P. falciparum with the apicoplast investigated as a potential target. Moreover, clindamycin, doxycycline, mirincamycin, and tigecycline were tested against S. mansoni schistosomula in vitro. Eravacycline showed the highest activity of all the tetracyclines in the 3-day and 6-day assays against P. falciparum clinical isolates in Gabon. Antibiotics tested against S. mansoni were shown to be inactive in our study, though mirincamycin exhibited minimal activity. These findings show the potential of novel antibiotics, especially eravacycline, as candidate antimalarial therapies and interventions in concomitant infections. In the second study, the in vitro potency of novel HDAC-inhibitors was evaluated against P. falciparum clinical isolates collected in Lambaréné, Gabon and surrounding area. The potency of 12 peptoid-based HDAC-inhibitors of human HDAC6 against asexual stages of P. falciparum clinical isolates was investigated. All HDAC-inhibitors demonstrated 50% inhibitory concentrations at nanomolar ranges. Peptoid-based HDAC6-inhibitors should be lead structures further evaluated for the development of antimalarial chemotherapeutics and to further investigate epigenetic regulators, including HDACs, as targets in Schistosoma parasites. In the final study, 16 antiplasmodial compounds were evaluated against S. mansoni, for alternative treatment strategies of Schistosoma infections. Pyronaridine, methylene blue, and 5 other antiplasmodial compounds were highly active in vitro against the larval stage schistosomula with IC50s below 10μM. Mice infected with S. mansoni at the prepatent stage were treated with pyronaridine which reduced the worm burden by 82% and cured 7 out of 12 animals, though the adult stages remained viable. Though, on the contrary, methylene blue inhibited adult worms by 60%, but did not cure the mice. As part of an observational pilot study in Gabon, children with S. haematobium infections were treated with pyronaridine-artesunate (Pyramax), resulting in a reduction of eggs excreted in urine from 10/10 ml to 0/10 ml, and 3 out of 4 children were cured. Pyronaridine and methylene blue should be further investigated as candidates in humans in clinical studies for schistosomiasis treatment, since both are already approved for human use. This thesis provides innovative data on novel inhibitors targeting organelles of prokaryotic descent, epigenetic regulators, and the hemozoin synthesis pathway in Plasmodium and Schistosoma parasites. These findings will contribute to further innovation of novel inhibitors used to increase control and elimination efforts for both parasitic diseases in endemic areas. Prospective work will further evaluate novel compounds in clinical studies in humans and potentially provide more information on the targets of each of these drug classes.
Download or read book Biochemical and Structural Characterization of Novel Drug Targets Regulating Polyamine Biosynthesis in the Human Malaria Parasite Plasmodium Falciparum written by Marni Williams and published by . This book was released on 2011 with total page 368 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Studies to Elucidate the Molecular Targets of Two Potent Antimalarial Benzoxaborole Compounds in Plasmodium Falciparum written by Ebere Irene Sonoiki and published by . This book was released on 2014 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: With increasing resistance of malaria parasites to available drugs, there is a great need for new antimalarials, ideally with novel mechanisms of action. We are investigating the antimalarial activity and mechanisms of action of benzoxaboroles, a novel class of boron-containing compounds. Compounds 3661, 1467 and related compounds demonstrated good activity in vitro against chloroquine-resistant Plasmodium falciparum and in vivo against murine Plasmodium berghei infection (compound 3661: IC50 37 nM against W2-strain P. falciparum, ED90 0.3 mg/kg against murine P.berghei; compound 1467: IC50 196 nM, ED90 7.4 mg/kg). In an attempt to characterize mechanisms of action, we selected for parasites with decreased sensitivity to 3661 and 1467 by culturing with step-wise increases in concentration of the compounds followed by whole genome sequencing. Sequencing of parasites selected for resistance to 1467 showed several SNPs in the editing domain of a predicted leucyl tRNA synthetase (LeuRS) gene (PF3D7_0622800) and in another gene of unknown function (PF3D7_1218100). Additionally, both compounds were tested for stage-specificity by incubation with test compounds for 8 hour intervals across the parasite erythrocytic life cycle. Both compounds were most active against trophozoite stage parasites. To further understand the mechanism of action of 1467 and the related compound 1474, the incorporation of 14[C] leucine in parasite cultures or parasite extracts including exogenous tRNA was assessed in the presence or absence of the compounds. Dose-dependent inhibition of both protein synthesis and LeuRS activity was observed for 1467 and 1474, but not 3661 or the control artemisinin, supporting different mechanisms for the different benzoxaboroles. For 3661, in vitro resistance selection was also achieved by culturing parasites in step-wise increasing concentration and in a single high concentration of the compound. Cross-resistance was not seen between parasites selected with 3661 and those selected with 1467. Whole genome sequencing of multiple clones selected for resistance to 3661 revealed several SNPs in a gene that codes for a homolog of mammalian cleavage and polyadenylation specificity factor (CPSF; PF14_0364). In summary, we offer strong evidence for unique antimalarial mechanisms of action for two benzoxaboroles, identifying two potential novel antimalarial drug targets. Further investigation of these novel benzoxaborole mechanisms is underway.
Download or read book Antimalarial Agents written by Graham L. Patrick and published by Elsevier. This book was released on 2020-05-30 with total page 624 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antimalarial Agents: Design and Mechanism of Action seeks to support medicinal chemists in their work toward antimalarial solutions, providing practical guidance on past and current developments and highlighting promising leads for the future. Malaria is a deadly disease which threatens half of the world’s population. Advances over several decades have seen vast improvements in the eff ectiveness of both preventative measures and treatments, but the rapid adaptability of the disease means that the ongoing search for improved and novel antimalarial drugs is essential. Beginning with a historical overview of malaria and antimalarial research, this book goes on to describe the biological aspects of malaria, highlighting the lifecycle of the parasite responsible for malaria, the problem of resistance, genetic mapping of the parasite’s genome, established drug targets, and potential drug targets for the future. This sets the scene for the following chapters which provide a detailed study of the medicinal chemistry of antimalarial agents, with a focus on the design of antimalarial drugs. Drawing on the knowledge of its experienced authors, and coupling historic research with current fi ndings to provide a full picture of both past and current milestones, Antimalarial Agents: Design and Mechanism of Action is a comprehensive yet accessible guide for all those involved in the design, development, and administration of antimalarial drugs, including student academic researchers, medicinal chemists, malaria researchers, and pharmaceutical scientists. Consolidates both past and current developments in the discovery and design of antimalarial drugs Presents content in a style that is both thorough and engaging, providing a supportive and guiding reference to students and researchers from interdisciplinary backgrounds Highlights drug targets currently considered to be the most promising for future therapies, and the classes of compounds that are currently being studied and perfected
Download or read book Development of Novel Chemical Biology Tools to Probe Malaria Parasite Physiology and Aid in Antimalarial Drug Discovery written by James Robbins Abshire and published by . This book was released on 2015 with total page 117 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria remains a major burden to global public health. Antimalarial drugs are a mainstay in efforts to control and eventually eradicate this disease. However, increasing drug resistance threatens to reverse recent gains in malaria control, making the discovery of new antimalarials critical. Antimalarial discovery is especially challenging due to the unique biology of malaria parasites, the scarcity of tools for identifying new drug targets, and the poorly understood mechanisms of action of existing antimalarials. Therefore, this work describes the development of two chemical biology tools to address unmet needs in antimalarial drug discovery. A particular challenge in antimalarial development is a shortage of validated parasite drug targets. Potent antimalarials with demonstrated clinical efficacy, like the aminoquinolines and artemisinins, represent a promising basis for rational drug development. Unfortunately, the molecular targets of these drugs have not been identified. While both are thought to interact with parasite heme, linking in vitro heme binding with drug potency remains challenging because labile heme is difficult to quantify in live cells. This work presents a novel genetically-encoded heme biosensor and describes its application to quantify labile heme in live malaria parasites and test mechanisms of antimalarial action. Another challenge is posed by the widespread malaria parasite Plasmodium vivax, which, unlike P. falciparum, cannot be propagated in vitro, hindering research into parasite biology and drug target identification. P. vivax preferentially invades reticulocytes, which are impractical to obtain in continuous supply. The basis for this invasion tropism remains incompletely understood, mainly because current tools cannot directly link molecular binding events to invasion outcomes. This work presents novel methods for immobilizing synthetic receptors on the red blood cell surface. These receptors are used in proof-of-concept experiments to investigate requirements for efficient invasion via a well-characterized P. falciparum invasion pathway, suggesting this method can be used to elucidate molecular mechanisms underlying parasite invasion tropisms. Future receptor designs could promote the invasion of P. vivax into mature red blood cells and potentially facilitate practical in vitro culture. Taken together, these tools present new opportunities for drug discovery to aid efforts in malaria control and eventual eradication.
Download or read book Probing Translational Regulation by the Malaria Parasite Plasmodium falciparum written by Christine Moore Sheridan and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structural and Functional Validation of S adenosylmethionine Decarboxylase as a Novel Drug Target in the Malaria Parasite Plasmodium Falciparum written by Dina Coertzen and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is considered the most prevailing human parasitic disease. Despite various chemotherapeutic interventions being available, the parasite responsible for the most lethal form of malaria, Plasmodium falciparum, is continuously developing resistance towards drugs targeted against it. This, therefore, necessitates the need for validation of new antimalarial development. Polyamine biosynthetic enzymes, particularly S-adenosylmethionine-L-decarboxylase (PfAdoMetDC), has been identified as a suitable drug target for protozoan parasitic diseases due to its essential role in cell proliferation. Furthermore, in Plasmodium polyamine biosynthesis, PfAdoMetDC is organised into a unique bifunctional complex with ornithine decarboxylase (PfAdoMetDC/ODC) covalently linked by a hinge region, distinguishing this enzyme as unique a drug target. However, inhibitors targeting this pathway have not been successful in clinical assessment, creating the need for further research in identifying novel inhibitors. This study focused on the structural and functional characterisation of protein-specific properties of the AdoMetDC domain in P. falciparum parasites, as well as identifying novel inhibitors targeting this enzyme as a potential antimalarial therapeutic intervention. In order to develop novel inhibitors specifically targeting PfAdoMetDC through a structure-based drug discovery approach, the three-dimensional structure is required. However, due to a lack of structural and functional characterisation, determination of the crystal structure has been challenging. Heterologous expression of monofunctional PfAdoMetDC was achieved from a wild-type construct of the PfAdoMetDC domain including the covalently linked hinge region. In chapter 2, deletion of a large non-homologous, low-complexity parasite-specific insert (A3) in monofunctional PfAdoMetDC resulted in an increased yield, purity and sample homogeneity, whilst maintaining protein functionality and structural integrity. However, truncation of the proposed non-essential hinge region resulted in low-level expression of insoluble protein aggregates and a complete loss of protein activity, indicating that the hinge region is essential for monofunctional PfAdoMetDC. However, in the absence of the three-dimensional PfAdoMetDC crystal structure, novel derivatives of a well-known AdoMetDC inhibitor, MDL73811, were tested for their activity against heterologous PfAdoMetDC, as well as their potency against P. falciparum parasites, in chapter 3. The compound Genz-644131 was identified as a lead inhibitor of PfAdoMetDC, however, the poor membrane permeability of the compound resulted in low in vitro activity. Drug permeability of Genz-644131 into P. falciparum infected erythrocytes and its potency was significantly improved by its encapsulation into a novel immunoliposome based drug delivery system. The results presented here provide essential information for development of a unique strategy in obtaining suffiecient levels of fully active recombinant PfAdoMetDC of sufficient purity for crystallisation studies and subsequent structure-based drug design efforts. The combination of Genz-644131 with the novel drug delivery system, which markedly improved its potency against PfAdoMetDC may proof to be a viable antimalarial chemotherapeutic strategy for future investigations.
Download or read book Structural Bioinformatics Applications in Preclinical Drug Discovery Process written by C. Gopi Mohan and published by Springer. This book was released on 2019-01-10 with total page 406 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book reviews the advances and challenges of structure-based drug design in the preclinical drug discovery process, addressing various diseases, including malaria, tuberculosis and cancer. Written by internationally recognized researchers, this edited book discusses how the application of the various in-silico techniques, such as molecular docking, virtual screening, pharmacophore modeling, molecular dynamics simulations, and residue interaction networks offers insights into pharmacologically active novel molecular entities. It presents a clear concept of the molecular mechanism of different drug targets and explores methods to help understand drug resistance. In addition, it includes chapters dedicated to natural-product- derived medicines, combinatorial drug discovery, the CryoEM technique for structure-based drug design and big data in drug discovery. The book offers an invaluable resource for graduate and postgraduate students, as well as for researchers in academic and industrial laboratories working in the areas of chemoinformatics, medicinal and pharmaceutical chemistry and pharmacoinformatics.
Download or read book Hydroxamic Acids written by Satya P. Gupta and published by Springer Science & Business Media. This book was released on 2013-09-30 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt: Satya P. Gupta's Hydroxamics Acids is the first book to compile invited articles written by international experts on the class of compounds hydroxamic acids. Found to possess a wide spectrum of biological activities, the hydroxamic acids are of interest to theoretical and experimental chemists who can study and make use of them in drug design and development. Chapters in this book provide a diverse and comprehensive coverage of this compound class and consequently this publication is a valuable resource for researchers in chemical, pharmaceutical and biological sciences.
Download or read book Antimalarial Agents written by Graham L. Patrick and published by Elsevier. This book was released on 2020-06-16 with total page 622 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antimalarial Agents: Design and Mechanism of Action seeks to support medicinal chemists in their work toward antimalarial solutions, providing practical guidance on past and current developments and highlighting promising leads for the future. Malaria is a deadly disease which threatens half of the world's population. Advances over several decades have seen vast improvements in the eff ectiveness of both preventative measures and treatments, but the rapid adaptability of the disease means that the ongoing search for improved and novel antimalarial drugs is essential. Beginning with a historical overview of malaria and antimalarial research, this book goes on to describe the biological aspects of malaria, highlighting the lifecycle of the parasite responsible for malaria, the problem of resistance, genetic mapping of the parasite's genome, established drug targets, and potential drug targets for the future. This sets the scene for the following chapters which provide a detailed study of the medicinal chemistry of antimalarial agents, with a focus on the design of antimalarial drugs. Drawing on the knowledge of its experienced authors, and coupling historic research with current fi ndings to provide a full picture of both past and current milestones, Antimalarial Agents: Design and Mechanism of Action is a comprehensive yet accessible guide for all those involved in the design, development, and administration of antimalarial drugs, including student academic researchers, medicinal chemists, malaria researchers, and pharmaceutical scientists. Consolidates both past and current developments in the discovery and design of antimalarial drugs Presents content in a style that is both thorough and engaging, providing a supportive and guiding reference to students and researchers from interdisciplinary backgrounds Highlights drug targets currently considered to be the most promising for future therapies, and the classes of compounds that are currently being studied and perfected
Download or read book Comprehensive Analysis of Parasite Biology written by Sylke Müller and published by John Wiley & Sons. This book was released on 2016-07-19 with total page 576 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written and edited by experts in the field, this book brings together the current state of the art in phenotypic and rational, target-based approaches to drug discovery against pathogenic protozoa. The chapters focus particularly on virtual compounds and high throughput screening, natural products, computer-assisted drug design, structure-based drug design, mechanism of action identification, and pathway modelling. Furthermore, state-of the art "omics" technologies are described and currently studied enzymatic drug targets are discussed. Mathematical, systems biology-based approaches are introduced as new methodologies for dissecting complex aspects of pathogen survival mechanisms and for target identification. In addition, recently developed anti-parasitic agents targeting particular pathways, which serve as lead compounds for further drug development, are presented.
Download or read book Epigenetic Drug Discovery written by Wolfgang Sippl and published by John Wiley & Sons. This book was released on 2019-03-25 with total page 504 pages. Available in PDF, EPUB and Kindle. Book excerpt: This broad view of epigenetic approaches in drug discovery combines methods and strategies with individual targets, including new and largely unexplored ones such as sirtuins and methyl-lysine reader proteins. Presented in three parts - Introduction to Epigenetics, General Aspects and Methodologies, and Epigenetic Target Classes - it covers everything any drug researcher would need in order to know about targeting epigenetic mechanisms of disease. Epigenetic Drug Discovery is an important resource for medicinal chemists, pharmaceutical researchers, biochemists, molecular biologists, and molecular geneticists.
