Download or read book New Strategies for Drug Discovery and Development for Plasmodium Falciparum written by and published by . This book was released on 2000 with total page 33 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. Recognizing this emerging crisis, it is necessary to identify new strategies for the identification and development of new antimalarials. The goal of this work is the development of a framework for antimalarial drug development into the 21st century. A new strategy for drug development is urgently needed. Current drugs are based on a small number of target molecules or lead compounds and in most cases the target of drug action is yet to be identified. Resistance is emerging rapidly and the mechanisms of resistance are poorly understood. The identification of new targets or new candidate drugs based on an understanding of the parasite biology are key elements in this new strategy. Clearly the development of a new antimalarial will require both basic and applied research working in concert with one another. The goal of this work is to use a molecular genetic approach both in the identification of new drug targets and in the investigation of mechanisms of drug resistance. The research has focused on the two objectives, namely the analysis of critical genes in the Plasmodium falciparum for their role in drug resistance and as potential new drug targets, including the analysis of gene expression in response to drug treatment using the method of Serial Analysis of Gene Expression and the use of DNA Chip technology in the analysis of the yeast heterologous system.

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 Drug Discovery in Africa written by Kelly Chibale and published by Springer Science & Business Media. This book was released on 2012-08-09 with total page 453 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drug discovery originating in Africa has the potential to provide significantly improved treatment of endemic diseases such as malaria, tuberculosis and HIV/AIDS. This book critically reviews the current status of drug discovery research and development in Africa, for diseases that are a major threat to the health of people living in Africa. Compiled by leading African and international experts, this book presents the science and strategies of modern drug discovery. It explores how the use of natural products and traditional medicines can benefit from conventional drug discovery approaches, and proposes solutions to current technological, infrastructural, human resources, and economic challenges, which are presented when attempting to engage in full-scale drug discovery. Topics addressed are varied; from African medicinal plants to marine bioprospecting, pharmacogenetics and the use of nanotechnology. This book brings together for the first time a collection of strategies and techniques that need to be considered when developing drugs in an African setting. It is an unprecedented and truly international effort, highlighting the remarkable effort made so far in the area of drug discovery research by African scientists, and scientists from other parts of the world working on African health problems.

Download or read book Development of a Dynamic Receptor based Pharmacophore Model of Plasmodium Falciparum Spermidine Synthase for Selective Inhibitor Identification written by Pieter Buys Burger and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria affects the daily lives of more than 2 billion people worldwide and has been estimated to result in 300-500 million clinical cases annually leading to approximately 2 million deaths, mainly caused by the most virulent malaria species, Plasmodium falciparum. The lack of a vaccine and the rapid emergence and spread of drug resistant strains of P. falciparum, necessitate the development of new antimalarials and the identification and validation of new parasite-specific therapeutic targets. Numerous studies directed at interfering with the polyamine biosynthetic pathway in P. falciparum have shown its potential as a target for the development of a new class of antimalarials. The essential nature of P. falciparum spermidine synthase (PfSpdSyn), an enzyme in the polyamine pathway of the parasite warranted the further investigation to find novel lead compounds. The high cost and attrition rate of drug discovery has resulted in the implementation of smart drug discovery platforms in both academia and industry. The strategy implemented in this study involved the development of a dynamic receptor-based pharmacophore model (DPM) of PfSpdSyn complemented by a knowledge-based rational design strategy. The use of pharmacophore models to identify lead compounds has become increasingly popular over the last decade and has been shown to be a reliable method in the drug discovery process. The development of a DPM allows for the incorporation of protein exibility within the drug design process. This methodology results in a wealth of information of the chemical space of the active site and was incorporated in designing new inhibitors against PfSpdSyn using a knowledge-based rational design strategy. The active site of PfSpdSyn was subdivided into four binding regions (DPM1-DPM4) to allow for the identi cation of fragments binding within these speci c binding regions. DPMs representative of the chemical characteristics of each binding region were constructed and subsequently screened against the drug-like subset of the ZINC database. From the screens a total of nine compounds were selected for in vitro testing, complementing each other in exploring specific active site binding characteristics. From these compounds a new lead compound N-(3-aminopropyl)-cyclohexylamine (NAC: Ki 2.8 ; M) was identified for PfSpdSyn. NAC was specifically designed to bind in both the putrescine and decarboxylated adenosylmethionine cavities by chemically bridging the catalytic center and was confirmed by kinetic studies. NAC shows great potential for lead optimization to increase its binding affinity. This study then paves the way for lead optimization and possibly the development of a novel antimalarial. The development of a DPM for PfSpdSyn has seen the establishment of this methodology in the Bioinformatics and Computational Biology Unit, Department of Biochemistry at the University of Pretoria. It can be concluded that the development of a DPM complemented by a knowledge-based rational design strategy is an effective approach for the identification of novel lead compounds in the presence of a 3D target structure. This paves the way for more studies on both malaria and other drug targets using DPMs. Copyright.

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 Antiprotozoal Drug Development and Delivery written by Alane Beatriz Vermelho and published by Springer Nature. This book was released on 2022-06-24 with total page 333 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book reviews new promising drug targets for Neglected Tropical Diseases (NTDs), with a special focus on antiprotozoal drugs against trpyanosomatids Trypanosoma cruzi and Leishmania spp. The book offers a comprehensive overview of the most recent studied targets, and it outlines classical and new treatments and delivery strategies. Expert contributors describe new methods of analysis and bio-prospecting for new compounds, and provide a critical perspective of the translational process used in the research and development of new drug candidates. The book will appeal not only to researchers, students and professionals interested in drug development to protozoan diseases, but also to medicinal chemists in general.

Download or read book Innovative Therapeutic and Immunomodulatory Strategies for Protozoan Infections written by Jorge Enrique Gomez-Marin and published by Frontiers Media SA. This book was released on 2019-11-04 with total page 177 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human protozoan infections are an important target for development of new vaccines and drugs. No completely efficacious vaccines for human protozoan infections are available and in the case of malaria resistance to the most efficacious antimalarials has become a global challenge. In ocular toxoplasmosis complete eradication of the body is not possible, exposing patients to new reactivations. The need of treatment or vaccines for and of less toxic drugs for Leishmania are urgent tasks for protozoologists research community. New research strategies have appeared that enlarged the possibilities for treatment and vaccine development. Reverse vaccinology, bioinformatic search of second use drug candidates and ex vivo analysis have afforded new fields for development.

Download or read book Global Report on Antimalarial Drug Efficacy and Drug Resistance written by and published by . This book was released on 2010 with total page 115 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report provides a comprehensive, global overview of antimalarial drug efficacy and the resistance of malaria parasites to the antimalarial medicines used between 2000 and June 2010. Policy-makers in national ministries of health will benefit from this document, as it provides both a global and a regional picture of the efficacy of the antimalarial medicines currently used in national treatment programmes. In addition, the report will be a reference for scientists, enhancing their understanding of the complexity of antimalarial drug resistance.

Download or read book Design of Hybrid Molecules for Drug Development written by Michael Decker and published by Elsevier. This book was released on 2017-04-05 with total page 354 pages. Available in PDF, EPUB and Kindle. Book excerpt: Design of Hybrid Molecules for Drug Development reviews the principles, advantages, and limitations involved with designing these groundbreaking compounds. Beginning with an introduction to hybrid molecule design and background as to their need, the book goes on to explore a range of important hybrids, with hybrids containing natural products, molecules containing NO- and H2S-donors, dual-acting compounds acting as receptor ligands and enzyme inhibitors, and the design of photoresponsive drugs all discussed. Drawing on practical case studies, the hybridization of molecules for development as treatments for a number of key diseases is then outlined, including the design of hybrids for Alzheimer's, cancer, and malaria. With its cutting-edge reviews of breaking developments in this exciting field, the book offers a novel approach for all those working in the design, development, and administration of drugs for a range of debilitating disorders. Highlights an approach unimpaired by the limitations of the classical search for lead structures - one of the core problems in modern drug development processes, making the content of high relevance for both academic and non-academic drug development processes Pulls together research and design techniques in a novel way to give researchers the best possible platform from which to review the approaches and techniques applied Compares the advantages and disadvantages of these compounds Includes the very latest developments, such as photoactivatable and photo-responsive drugs

Download or read book Genomics and Transcriptomics Approaches to Understanding Drug Resistance Mechanisms in the Malaria Parasite Plasmodium Falciparum written by Justin Allan Gibbons and published by . This book was released on 2019 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the gene with the strongest association with artemisinin resistance, and the potential genetic mechanisms associated with resistance to atovaquone, another widely used antimalarial. To precisely study the transcriptome characteristics of an isogenic k13 dysregulation mutant and wild type strain, I developed a new computational algorithm called Dephasing Identifier (DI) that is capable of identifying the genes dysregulated in cell cycle shifts. DI is designed to solve the problem of pinpointing important patterns in complex genomics data with temporal sequences that cannot be resolved by standard pair-wise comparison methods, by using an innovative method that leverages external reference data for systematic comparisons. In the k13 study, I demonstrated that the algorithm identifies co- regulated gene sets that have consistent annotated functions. The DI algorithm successfully identified aberrantly early DNA replication as the driving process of transcriptome changes in the mutant. To understand genome-wide changes that occurred in a set of atovaquone resistance stains, I analyzed whole genome sequencing data previously generated for a P. falciparum strain that underwent in vitro atovaquone selection to create atovaquone resistant strains. I systematically analyzed the genomes of these strains to search for significant genetic changes associated with atovaquone resistance; and used stringent criteria to identify genes involved in regulating transcription and protein modifications as acquiring non- synonymous mutations. Additionally, copy number variations in plasmepsin genes, a family known to be involved in resistance, were found in the resistant strains. In summary, genomics and transcriptomics technologies can be used to rapidly identify resistance mechanisms allowing for faster adjustment of current containment strategies. Future research on the critical targets identified in this study can aid new drug discovery efforts and novel control strategies.

Download or read book Advances in Malaria Research written by Deepak Gaur and published by John Wiley & Sons. This book was released on 2016-12-27 with total page 611 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 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 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 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 Harnessing Evolutionary Fitness in Plasmodium Falciparum for Drug Discovery and Suppressing Resistance written by Leila Saxby Ross and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a preventable and treatable disease caused by infection with Plasmodium parasites. Complex socioeconomic and political factors limit access to vector control and antimalarial drugs, and an estimated 600,000 people die from malaria every year. Rising drug resistance threatens to make malaria untreatable. As for all new traits, resistance is limited by fitness, and a small number of pathways are heavily favored by evolution. These pathways are targets for drug discovery. Pairing compounds active against the wild-type and the small emerging resistant population, a strategy we termed "targeting resistance," could block the rise of competitively viable resistance.

Download or read book Global Technical Strategy for Malaria 2016 2030 written by World Health Organization and published by World Health Organization. This book was released on 2015-11-04 with total page 35 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Health Organization's Global Technical Strategy for Malaria 2016- 2030 has been developed with the aim to help countries to reduce the human suffering caused by the world's deadliest mosquito-borne disease. Adopted by the World Health Assembly in May 2015 it provides comprehensive technical guidance to countries and development partners for the next 15 years emphasizing the importance of scaling up malaria responses and moving towards elimination. It also highlights the urgent need to increase investments across all interventions - including preventive measures diagnostic testing treatment and disease surveillance- as well as in harnessing innovation and expanding research. By adopting this strategy WHO Member States have endorsed the bold vision of a world free of malaria and set the ambitious new target of reducing the global malaria burden by 90% by 2030. They also agreed to strengthen health systems address emerging multi-drug and insecticide resistance and intensify national cross-border and regional efforts to scale up malaria responses to protect everyone at risk.