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 Reflections on a Century of Malaria Biochemistry written by Irwin Sherman and published by Academic Press. This book was released on 2011-08-29 with total page 417 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is one of the most common infectious diseases and an enormous public health problem. Each year it causes disease in approximately 650 million people and kills between 1 and 3 million, most of them young children in Sub-Saharan Africa. This book provides an overview of the research that has been done in malaria biochemistry in the quest to find a cure. It discusses how our understanding has helped us to develop better diagnostics and novel chemotherapies. Researchers will find having all of this information in one volume, annotated with personal reflections from a leader in the field, invaluable given the big push being made on various fronts to use the latest drug discovery tools to attack malaria and other developing country diseases. Reviews the past 100 years of malaria biochemistry research providing researchers with an overview of the investigations that have been undertaken in this field Chronicles both biochemical successes and failures

Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.

Download or read book Advances in Malaria Research written by Deepak Gaur and published by John Wiley & Sons. This book was released on 2016-11-30 with total page 1116 pages. Available in PDF, EPUB and Kindle. Book excerpt: Thoroughly reviews our current understanding of malarial biology Explores the subject with insights from post-genomic technologies Looks broadly at the disease, vectors of infection, and treatment and prevention strategies A timely publication with chapters written by global researchers leaders

Download or read book Emergence of In Vitro 3D Systems to Model Human Malaria written by Kasem Kulkeaw and published by Springer Nature. This book was released on 2023-05-29 with total page 99 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book illustrates the importance and advances of the disease model for malaria, a globally affected public health problem. This book provides comprehensive information on the malaria biology in a liver and all in vitro platforms for liver-stage malaria, including principles, protocols, applications for disease modeling and drug screening, and their limitations. The initial chapter describes the basis of stem cells in liver generation during development and in adults. The subsequent chapters highlight recent and emerging advances in liver organoid and liver-on-a-chip in modeling malaria. The book presents current protocols and methods to generate liver organoid and liver-on-a-chip together with their advantages and limitations. Toward the end, the book examines the humanized mouse model of liver-stage malaria using ectopic artificial livers regarding novel readout modalities. The recent advancement and challenges in combining liver-on-a-chip technology with biosensors are highlighted for assessing hepatocyte development viability and functions. The book elucidates the potential of these 3D models to understand the biological complexity of cellular and molecular mechanisms involved in Plasmodium development in the liver, toolboxes to investigate parasite deployment in the 3D models, and to implement in drug discovery. Finally, the book discusses the future directions and challenges in the applications of liver organoids and liver on-chip in the biology of live-stage malaria. This book is helpful for researchers and scientists in the field of parasitology, cell biology, tissue engineering, and pharmacology.​

Download or read book Synthesis in Vitro Characterization and Applications of Novel 8 aminoquinoline Fluorescent Probes written by Adonis C. McQueen and published by . This book was released on 2017 with total page 103 pages. Available in PDF, EPUB and Kindle. Book excerpt: ABSTRACT: Malaria is a parasitic disease that is caused by the plasmodium parasite. Plasmodium infection has affected man for thousands of years. With advances in drug discovery over the past century, malaria has evolved to possess resistance to most mainline therapeutics. This war of drug discovery vs plasmodium evolution continues to be fought to this very day, with attempts to eradicate malaria worldwide. Frontline treatments such as chloroquine, artemisinin, and atovaquone/proguanil have all seen parasitic resistance in strains of P. vivax as well as P. falciparum. While plasmodium possesses resistance to most classes of anti-malarials, the 8-aminoquinoline (8-AQ) class has seen minimal resistance development. 8-AQs have been shown to be effective against erythrocytic and exo-erythrocytic forms of plasmodium, and are often given in combination with a blood schizonticide such as chloroquine or artemisinin. These combinations clear all forms of plasmodium infection. With 8-AQs unique set of anti-malarial properties and the advent of increased drug resistance to other drugs, much research is being done to understand 8-AQs mechanism of action and toxicity. 8-AQ use is limited due to inducing extreme hemolytic anemia in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is the only 8-AQ molecule available on the market with tafenoquine, an analog primaquine, currently in phase III clinical trials. It is believed that if the mechanism of action and toxicity of the 8-AQs are understood, then we can create new generation anti-malarials that will maintain the unique action of 8-AQs while reducing their toxicity. Studies have shown that 8-AQ mechanism of action has been attributed to the generation of unstable metabolites that induce ROS production in the parasite, as well as mitochondrial swelling. While there is some evidence suggesting molecular targets of 8-AQs, the actual target is still unknown. When 8-AQs is given in combination with chloroquine, a synergistic effect is observed. While chloroquine has no activity against liver stages, it still somehow potentiates primaquines activity in those stages. This mechanism of synergy in liver stages is not well understood, and its understanding can give us increased understanding of basic plasmodium biology in the liver. Additionally, more information about the mechanisms of action vii of both chloroquine and primaquine could be elucidated. Tagging drugs with fluorescent probes is a technique that can give much information about the drugs pharmacological activity in vitro, and sometimes in vivo as well. Such an approach has been used for various disease states such as HIV and cancer. Malaria is no exception; fluorescent probes of artemisinin and chloroquine have been used to examine resistance mechanisms to both molecules. In addition to 8-AQs, there are other older antimalarials that have received attention recently due to increases in resistance. Menoctone, a hydroxynapthoquinone that subsequently lead to the discovery of atovaquone, has recently gained increased attention because of its similarities to atovaquone. Research surrounding menoctone was abandoned due to the discovery of more efficacious compounds. Similar to 8-AQs, understanding the mechanisms of action and resistance to menoctone could give us much more information about plasmodium responses to this class of compounds. This understanding could potentially lead to the discovery of novel therapeutics. To understand mechanisms of action and synergy of 8-AQs, we report the creation of novel fluorescent probes of the 8-AQ molecules primaquine and tafenoquine. The organic synthesis was designed and characterization was confirmed by NMR and high resolution mass spectra, and the fluorescent properties were examined using absorbance and steady-state emission experiments. We found that the anti-malarial, anti-leishmaniasis, and cytotoxic properties of these novel probes were similar to the parent compounds. These probes localized in the cytoplasm of infected parasites in vitro. We also attempted to view their localization in liver stage infection, and investigated the synergistic combination of 8-AQs with chloroquine and quinine. Menoctone resistance was induced in vivo to determine mechanisms of resistance. Cross resistance to atovaquone was observed, and the mutation responsible for resistance was also found.

Download or read book Antimalarial Drug Discovery and Target Identification from Phenotypic High throughput Screening Hits written by Matthew Abraham and published by . This book was released on 2020 with total page 104 pages. Available in PDF, EPUB and Kindle. Book excerpt: The drive to propagate a species genes is among the strongest biological forces, shared by humans and pathogens alike. For pathogens like Plasmodium parasites, the etiological agent of human malaria, self-preservation comes at the cost of hundreds of thousands of human lives annually. Between 2000 and 2016, worldwide cases of malaria were progressively declining. Although there are many causes for the recent increase in global malaria cases, parasite drug resistance is a likely contributor. Thus, research is desperately needed to identify druggable targets and develop novel therapeutics capable of more than symptom alleviation. This dissertation highlights the use of key strategies that have resulted in new preclinical drug candidates, namely the systematic investigation of vast small molecule libraries. In Chapter 1, the investigation of more than 100 marine derived natural products identified six compounds with promising antiparasitic activity and selectivity relative to the host cell. Additionally, this chapter describes the successful target identification of choice screening hits, such as hectochlorin and its newly validated target, actin. In Chapter 2 high throughput screening methods are embraced to explore the activity of nearly 70,000 small molecules, testing them, with collaborators, against all malaria parasite stages that dwell in the human host. Hundreds of these molecules are discovered to have activity against one or more of these stages. Studies in collaboration with Manu Vanaerschot show the target of one such molecule acting within the mitochondrial electron transport chain, against cytochrome bc1. Despite affecting a well-characterized drug target in Plasmodium, this target rediscovery legitimizes our strategy for antimalarial hit selection from untested chemical libraries. Because drug target discovery is vital to the development of novel therapeutics, and can guide drug design to minimize the likelihood of off target effects, Chapter 3 describes the search for the target of a potent asexual blood stage (ABS) inhibitor. Here, the protein cytoplasmic isoleucyl-tRNA synthetase (PF3D7_1332900) is shown as the target of a drug-like scaffold, TCMDC-124553. This protein was previously shown to be critical in P. falciparum ABS, and our data also suggest it is essential in the liver stage of infection as well.

Download or read book Antimalarial Natural Products written by A. Douglas Kinghorn and published by Springer. This book was released on 2023-01-05 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume begins with a short history of malaria and follows with a summary of its biology. It then traces the fascinating history of the discovery of quinine for malaria treatment, and then describes quinine’s biosynthesis, its mechanism of action, and its clinical use, concluding with a discussion of synthetic antimalarial agents based on quinine’s structure. It also covers the discovery of artemisinin and its development as the source of the most effective current antimalarial drug, including summaries of its synthesis and biosynthesis, its mechanism of action, and its clinical use and resistance. A short discussion of other clinically used antimalarial natural products leads to a detailed treatment of additional natural products with significant antiplasmodial activity, classified by compound type. Although the search for new antimalarial natural products from Nature’s combinatorial library is challenging, it is very likely to yield new antimalarial drugs. This book thus ends by identifying ten natural products with development potential as clinical antimalarial agents.

Download or read book Antimalarial Drug Design written by Alexandre Lawrenson and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a life-threatening disease which is responsible for roughly one million deaths annually. Previous successes in attempting to eradicate the disease have only been short lived, owing to the increased development of resistance in the parasite. There is a continued need for novel compounds which act at novel therapeutic targets, with the Plasmodium falciparum cytochrome bc1 complex (Pfbc1) representing one such target. Its inhibition halts the biochemical generation of ATP, thus resulting in parasite cell death. Work described in this thesis was concerned with utilising molecular modelling, synthesis and biological testing to develop novel antimalarial compounds, which selectively inhibit this target. The structural details of a number of compounds known to be active or inactive against Pfbc1 were used in combination with six different ligand based virtual screening techniques, and applied to the ZINC lead like library of compounds to identify potential chemotypes active against malaria. These methods included fingerprint similarity searching, principal component analysis, and naïve Bayesian classification. The hits from each of these methods were merged and formed part of a consensus analysis in which compounds identified across several methods were deemed of more interest than those which appeared less frequently. Each molecule was given a score based on its occurrence in the virtual screening methods and also its physicochemical properties. Compounds were filtered to remove those with unfavourable chemical properties, or which contained known toxicophores. 19 compounds were ultimately purchased and tested in vitro against the 3D7 strain of the malaria parasite. 5 of the compounds reported single digit μM IC50 values, with each containing novel structural chemotypes. The lead candidate contained a benzothiazole core, and reported an IC50 value against 3D7 of 4.53 ± 1.86 μM. Additional testing showed the compounds to be inactive against bovine bc1, which is promising as strong bovine bc1 inhibition has been shown to be indicative of cardiotoxicity in humans. Molecular docking was extensively employed to rationalise the activity of Pfbc1 inhibitors such as atovaquone and HDQ. A number of quinolone containing compounds were also subject to docking, with key observations made with regard to interactions thought to be crucial to their antimalarial activity. The hits from LBVS were also the focus of docking, further supporting their potential as Pfbc1 inhibitors. QSARs were developed for a series of 4-aminoquinoline compounds which had been tested against both the NF54 and K1 strains of malaria. MLR, PLS and kNN machine learning methods were investigated, with molecular descriptors contained within valid models interpreted. Significant models were identified and shown to have strong predictive abilities for both strains. QSAR models were similarly developed for a series of thiazolide compounds with activity against hepatitis C. SVM was found to give a significant model which was able to predict the cell safety of the thiazolide derivatives. The rational design of the novel pyrroloquinolone chemotype led to the synthesis of 7 synthetic analogues to investigate its SAR, via alkylation and Winterfeldt oxidation reactions. The compounds reported 3D7 activity values between 75 nM and 1.02 μM, with molecular docking supporting their potential for Qo binding and thus Pfbc1 inhibition.

Download or read book World malaria report 2017 written by World Health Organization and published by World Health Organization. This book was released on 2018-02-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Malaria Report 2017 presents a comprehensive state of play in global progress in the fight against malaria up to the end of 2016. It tracks progress in investments in malaria programs and research, malaria prevention, diagnosis and treatment, surveillance, trends in malaria disease burden, malaria elimination, and threats in tackling malaria and safeguarding the investments made. The report draws on data from 91 countries and areas with ongoing malaria transmission. The information is supplemented by data from national household surveys and databases held by other organizations. This year's report shows that after an unprecedented period of success in global malaria control, progress has stalled. In 2016, there were an estimated 216 million cases of malaria, an increase of about 5 million cases over 2015. Deaths reached 445,000, a similar number to the previous year.

Download or read book Global Infectious Disease Surveillance and Detection written by Institute of Medicine and published by National Academies Press. This book was released on 2007-11-11 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: Early detection is essential to the control of emerging, reemerging, and novel infectious diseases, whether naturally occurring or intentionally introduced. Containing the spread of such diseases in a profoundly interconnected world requires active vigilance for signs of an outbreak, rapid recognition of its presence, and diagnosis of its microbial cause, in addition to strategies and resources for an appropriate and efficient response. Although these actions are often viewed in terms of human public health, they also challenge the plant and animal health communities. Surveillance, defined as "the continual scrutiny of all aspects of occurrence and spread of a disease that are pertinent to effective control", involves the "systematic collection, analysis, interpretation, and dissemination of health data." Disease detection and diagnosis is the act of discovering a novel, emerging, or reemerging disease or disease event and identifying its cause. Diagnosis is "the cornerstone of effective disease control and prevention efforts, including surveillance." Disease surveillance and detection relies heavily on the astute individual: the clinician, veterinarian, plant pathologist, farmer, livestock manager, or agricultural extension agent who notices something unusual, atypical, or suspicious and brings this discovery in a timely way to the attention of an appropriate representative of human public health, veterinary medicine, or agriculture. Most developed countries have the ability to detect and diagnose human, animal, and plant diseases. Global Infectious Disease Surveillance and Detection: Assessing the Challenges-Finding Solutions, Workshop Summary is part of a 10 book series and summarizes the recommendations and presentations of the workshop.

Download or read book World Malaria Report 2019 written by World Health Organization and published by . This book was released on 2019-08-28 with total page 224 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Malaria Report 2019 provides a comprehensive update on global and regional malaria data and trends. The report tracks investments in malaria programs and research as well as progress across all intervention areas: prevention, diagnosis, treatment, elimination, and surveillance. It also includes dedicated chapters on the consequences of malaria on maternal infant and child health the "High Burden to High Impact" approach as well as biological threats to the fight against malaria. The 2019 report is based on information received from more than 80 countries and areas with ongoing malaria transmission. This information is supplemented by data from national household surveys and databases held by other organizations.

Download or read book Natural Remedies in the Fight Against Parasites written by Hanem Khater and published by BoD – Books on Demand. This book was released on 2017-07-12 with total page 250 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book emphasizes past and current research efforts about principles of natural control of major parasites affecting humans, animals, and crops. Each chapter is a complete and integrated subject that presents a problem and confers on the safe alternatives to chemicals. This book discusses and updates information about three major topics of natural remedies. The first topic is represented in a chapter outlining important information on biological control of parasites, the second topic is represented in three chapters dealing with botanicals as promising antiparasitic agents, and the last four chapters deal with miscellaneous control strategies against parasites. This easily readable book is designed precisely for students as well as professors linked with the field of parasitic control. We enhanced words with breathing areas in the form of graphical abstracts, figures, photographs, and tables.

Download or read book Rodent Malaria written by R. Killick-Kendrick and published by Elsevier. This book was released on 2012-12-02 with total page 435 pages. Available in PDF, EPUB and Kindle. Book excerpt: Rodent Malaria reviews significant findings concerning malaria parasites of rodents, including their taxonomy, zoogeography, and evolution, along with life cycles and morphology; genetics and biochemistry; and concomitant infections. This volume is organized into eight chapters and begins by sketching out the history of the discovery of rodent as well as aspects of parasitology, immunology, and chemotherapy. These concepts are investigated two decades following Ignace Vincke's major discovery and Meir Yoeli's successful establishment of the method of cyclical transmission of the parasite. The following chapters focus on the taxonomy and systematics of the subgenus Vinckeia, with reference to the concepts of species and subspecies of animals and the degree to which they apply to malaria parasites, in particular to those of rodents. The discussion then shifts to how the rodent malaria parasites provide a unique insight into the subcellular organization of Plasmodium species, the use of rodent malaria as an experimental model to study immunological responses, and infectious agents that interact with malaria parasites. The book concludes with a chapter on malaria chemotherapy, with emphasis on the value of rodent malaria in antimalarial drug screening and the use of antimalarial drugs as biological probes. This book will be of interest to protozoologists and physicians as well as those from other disciplines including biochemistry, immunology, pharmacology, cell biology, and genetics.

Download or read book Vector Biology Ecology and Control written by Peter W. Atkinson and published by Springer Science & Business Media. This book was released on 2009-12-12 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mir S. Mulla joined the faculty of the Entomology Department at the University of California, Riverside in 1956, only two years after the Riverside campus was established as an independent campus within the University of California system. Prior to his appointment, Mir received his B.S. from Cornell University and then moved to the University of California, Berkeley to pursue his graduate studies. His Ph.D. from Berkeley, awarded in 1955, completed his formal American education which was the purpose of his immigration from his native Kandahar in Afghanistan. In his over 50 years at Riverside, Mir has made an incalculable impact on vector biology both within the United States and in developing countries throughout the world. Within Southern California, Mir’s basic and applied research led to the rapid and sustainable control of mosquitoes and eye gnats in the Coachella Valley and so directly enabled this region to grow to the thriving, large community it is today. In 2006 his efforts in facilitating the development of the low desert of southern California were recognized through the dedication of the Mir S. Mulla Biological Control Facility by the Coachella Valley Mosquito and Vector Control District. His success has been so profound that it remains somewhat cryptic to the many who now reside in, visit, and enjoy, this region of California, oblivious to the insect problems that severely restrained development until Mir and his students ?rst applied their expertise many decades ago.

Download or read book Science the Endless Frontier written by Vannevar Bush and published by Princeton University Press. This book was released on 2021-02-02 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt: The classic case for why government must support science—with a new essay by physicist and former congressman Rush Holt on what democracy needs from science today Science, the Endless Frontier is recognized as the landmark argument for the essential role of science in society and government’s responsibility to support scientific endeavors. First issued when Vannevar Bush was the director of the US Office of Scientific Research and Development during the Second World War, this classic remains vital in making the case that scientific progress is necessary to a nation’s health, security, and prosperity. Bush’s vision set the course for US science policy for more than half a century, building the world’s most productive scientific enterprise. Today, amid a changing funding landscape and challenges to science’s very credibility, Science, the Endless Frontier resonates as a powerful reminder that scientific progress and public well-being alike depend on the successful symbiosis between science and government. This timely new edition presents this iconic text alongside a new companion essay from scientist and former congressman Rush Holt, who offers a brief introduction and consideration of what society needs most from science now. Reflecting on the report’s legacy and relevance along with its limitations, Holt contends that the public’s ability to cope with today’s issues—such as public health, the changing climate and environment, and challenging technologies in modern society—requires a more capacious understanding of what science can contribute. Holt considers how scientists should think of their obligation to society and what the public should demand from science, and he calls for a renewed understanding of science’s value for democracy and society at large. A touchstone for concerned citizens, scientists, and policymakers, Science, the Endless Frontier endures as a passionate articulation of the power and potential of science.

Download or read book Innovations and Implementations of Computer Aided Drug Discovery Strategies in Rational Drug Design written by Sanjeev Kumar Singh and published by Springer Nature. This book was released on 2021-02-02 with total page 334 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents various computer-aided drug discovery methods for the design and development of ligand and structure-based drug molecules. A wide variety of computational approaches are now being used in various stages of drug discovery and development, as well as in clinical studies. Yet, despite the rapid advances in computer software and hardware, combined with the exponential growth in the available biological information, there are many challenges that still need to be addressed, as this book shows. In turn, it shares valuable insights into receptor-ligand interactions in connection with various biological functions and human diseases. The book discusses a wide range of phylogenetic methods and highlights the applications of Molecular Dynamics Simulation in the drug discovery process. It also explores the application of quantum mechanics in order to provide better accuracy when calculating protein-ligand binding interactions and predicting binding affinities. In closing, the book provides illustrative descriptions of major challenges associated with computer-aided drug discovery for the development of therapeutic drugs. Given its scope, it offers a valuable asset for life sciences researchers, medicinal chemists and bioinformaticians looking for the latest information on computer-aided methodologies for drug development, together with their applications in drug discovery.