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Combinative Strategy To Advance Target Based Anticryptosporidial Drug Discovery

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Combinative Strategy To Advance Target Based Anticryptosporidial Drug Discovery

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Author : Jubilee Ajiboye
language : en
Publisher:
Release Date : 2025

Combinative Strategy To Advance Target Based Anticryptosporidial Drug Discovery written by Jubilee Ajiboye and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2025 with CRISPR-associated protein 9 categories.

Cryptosporidiosis is a prevalent diarrheal disease characterized by infection of the small intestine by apicomplexan Cryptosporidium parasites. These intestinal parasites effectuate life-threatening diarrhea in young children and immunocompromised patients such as those on long-term immunosuppressants, or people living with HIV/AIDS. There are presently no vaccines to prevent cryptosporidiosis in humans. Unfortunately, the only FDA-approved treatment, nitazoxanide, lacks efficacy in immunocompromised patients but shows moderate efficacy in children, populations in which cryptosporidiosis is most severe and persistent. To engage the obvious paucity in the availability of novel anti-Cryptosporidium therapeutics, large-scale phenotypic screenings of compounds made available by Merck KGaA, Darmstadt, Germany, led to the identification of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hsPDE-V) and 1,5-naphthyridine phosphatidylinositol-4 kinase (PI4K) inhibitors with potent in vitro anticryptosporidial characteristics and in vivo efficacy following oral administration in C. parvum-infected immunocompromised mouse models of cryptosporidiosis. The lead phosphodiesterase inhibitor (PDEi) and phosphatidylinositol-4-kinase inhibitor (PI4Ki) series showed comparable anti-C. parvum and C. hominis potency, are fast-acting in tissue culture, and have minimal off-target effects in a preliminary safety screening assay panel. Our main objective was to validate the molecular targets of the novel PDEis and PI4Kis lead series in Cryptosporidium. By extension, we sought to uncover the mode-of-action of these novel lead series in C. parvum and highlight important target-based strategies that can be exploited for drug target identification in anticryptosporidial drug discovery. We demonstrated the mode-of-action of the lead series by employing life-cycle phenotypic assays which identified the parasite egress stage as the key life stage blocked by the PDEi and PI4Ki series. Subsequently, we utilized in vitro enzyme assays to confirm on-target engagement of our lead PDEis and PI4Kis against recombinant CpPDE1/CpPDE3 and CpPI4K enzymes, respectively. Guided by in silico analyses, we identified two residues (Val900 and His884) in the CpPDE1 active site predicted to be important for pyrazolopyrimidine PDEi binding. We produced a CRISPR-engineered C. parvum CpPDE1-V900A transgenic strain which exhibited altered susceptibility to our lead PDEi series, providing genetic support for CpPDE1-pyrazolopyrimidine PDEi interaction. Our findings suggest that CpPDE1, a validated pyrazolopyrimidine molecular target, can be exploited for target-based lead optimization in our anticryptosporidial drug development scheme. Furthermore, to genetically validate CpPI4K as a molecular target of the novel naphthyridine PI4Ki lead series, we overexpressed the wild-type CpPI4K gene in wild-type C. parvum to confirm the development of a resistance phenotype in the CpPI4K over-expressing transgenic strain. The expression of an additional copy of the wild-type CpPI4K gene conferred a moderate resistance phenotype in the presence of a naphthyridine PI4Ki and a separate imidazopyrazine PI4Ki by about 3-fold. These results provide compelling evidence that CpPI4K is a molecular target of the imidazopyrazine and novel naphthyridine PI4Ki lead series. In summary, we have identified and validated CpPI4K and CpPDE1 as molecular targets of our PI4Ki and PDEi lead series, respectively. Our target identification efforts on CpPDE1 marks the first characterization of the CpPDE1 as a druggable target in C. parvum. Meanwhile, our genetic validation of CpPI4K druggability will build on existing research in the anti-Cryptosporidium drug discovery field. Collectively, the results from this work will inform medicinal chemistry lead optimization efforts to advance anticryptosporidial drug development.

Insilico Identification And Optimization Of Natural Inhibitors For Drug Target Sites In Cryptosporidium Parvum

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Author : Dr. Pratibha Teotia
language : en
Publisher: Manojvm Publishing House
Release Date :

Insilico Identification And Optimization Of Natural Inhibitors For Drug Target Sites In Cryptosporidium Parvum written by Dr. Pratibha Teotia and has been published by Manojvm Publishing House this book supported file pdf, txt, epub, kindle and other format this book has been release on with Fiction categories.

Now day’s computer-aided drug design considered as a powerful method to design very specific lead compounds that can be developed as drug molecules. Using different in-silico tools, a target is selected and then its structure is defined and determined. After that new chemical/ synthetic compounds can be designed in-silico on the basis of combinatorial chemistry or chosen from an already available chemical library of molecules or library of molecules is generated from a subset of small molecules on the basis of docking and scoring against the particular target. In this study, I attempt to generate 2D QSAR model using small pIC50 values for thirty-eight benzoxazole derivatives binding with C. parvum IMPDH protein resulting correlation coefficient value R2/r2 is 0.7948. Docking results show that out of 38 benzoxazole derivatives, four compounds are most active. The present examination may give the data about potential derivatives of Benzoxazole as chemotherapeutic operators to battle against the expanding weight of Cryptosporidiosis infections.

Kucers The Use Of Antibiotics Sixth Edition

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Author : M Lindsay Grayson
language : en
Publisher: CRC Press
Release Date : 2010-10-29

Kucers The Use Of Antibiotics Sixth Edition written by M Lindsay Grayson and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-10-29 with Medical categories.

'I am unaware of any textbook which provides such comprehensive coverage of the field and doubt that this work will be surpassed in the foreseeable future, if ever!' From the foreword by Robert C. Moellering, Jr., M.D, Shields Warren-Mallinckrodt Professor of Medical Research, Harvard Medical School, USA Kucers' The Use of Antibiotics is the leading major reference work in this vast and rapidly developing field. More than doubled in length compared to the fifth edition, the sixth edition comprises 3000 pages over 2-volumes in order to cover all new and existing therapies, and emerging drugs not yet fully licensed. Concentrating on the treatment of infectious diseases, the content is divided into 4 sections: antibiotics, anti-fungal drugs, anti-parasitic drugs and anti-viral drugs, and is highly structured for ease of reference.Within each section, each chapter is structured to cover susceptibility, formulations and dosing (adult and paediatric), pharmacokinetics and pharmacodynamics, toxicity and drug distribution, detailed discussion regarding clinical uses, a feature unique to this title. Compiled by an expanded team of internationally renowned and respected editors, with a vast number of contributors spanning Europe, Africa, Asia, Australia, South America, the US and Canada, the sixth edition adopts a truly global approach. It will remain invaluable for anyone using antimicrobial agents in their clinical practice and provides in a systematic and concise manner all the information required when treating infections requiring antimicrobial therapy. Kucers' The Use of Antibiotics is available free to purchasers of the books as an electronic version on line or on your desktop: It provides access to the entire 2-volume print material It is fully searchable, so you can find the relevant information you need quickly Live references are linked to PubMed referring you to the latest journal material Customise the contents - you can highlight sections and make notes Comments can be shared with colleagues/tutors for discussion, teaching and learning The text can also be reflowed for ease of reading Text and illustrations copied will be automatically referenced to Kucers' The Use of Antibiotics

Logan Turner S Diseases Of The Nose Throat And Ear 10ed

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Author : Arthur Turner
language : en
Publisher: CRC Press
Release Date : 1987-12-30

Logan Turner S Diseases Of The Nose Throat And Ear 10ed written by Arthur Turner and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 1987-12-30 with Medical categories.

Innovations And Implementations Of Computer Aided Drug Discovery Strategies In Rational Drug Design

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Author : Sanjeev Kumar Singh
language : en
Publisher: Springer Nature
Release Date : 2021-02-02

Innovations And Implementations Of Computer Aided Drug Discovery Strategies In Rational Drug Design written by Sanjeev Kumar Singh and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-02-02 with Science categories.

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.

Antibody Drug Conjugates

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Author : Kenneth J. Olivier, Jr.
language : en
Publisher: John Wiley & Sons
Release Date : 2016-11-14

Antibody Drug Conjugates written by Kenneth J. Olivier, Jr. and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016-11-14 with Medical categories.

Providing practical and proven solutions for antibody-drug conjugate (ADC) drug discovery success in oncology, this book helps readers improve the drug safety and therapeutic efficacy of ADCs to kill targeted tumor cells. • Discusses the basics, drug delivery strategies, pharmacology and toxicology, and regulatory approval strategies • Covers the conduct and design of oncology clinical trials and the use of ADCs for tumor imaging • Includes case studies of ADCs in oncology drug development • Features contributions from highly-regarded experts on the frontlines of ADC research and development

Combination Therapy Against Multidrug Resistance

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Author : Mohmmad Younus Wani
language : en
Publisher: Academic Press
Release Date : 2020-04-30

Combination Therapy Against Multidrug Resistance written by Mohmmad Younus Wani and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-04-30 with Medical categories.

Combination Therapy against Multidrug Resistance explores the potential of combination therapy as an efficient strategy to combat multi-drug resistance. Multidrug resistance (MDR) occurs when microorganisms such as bacteria, fungi, viruses, and parasites are excessively exposed to antimicrobial drugs such as antibiotics, antifungals, or antivirals, and in response the microorganism undergoes mutations or develops different resistance mechanisms to combat the drug for its survival. MDR is becoming an increasingly serious problem in both developed and developing nations. Bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat, and the same is true for a variety of other diseases. Combination therapy proves to be a promising strategy as it offers potential benefits such as a broad spectrum of efficacy, greater potency than the drugs used in monotherapy, improved safety and tolerability, and reduction in the number of resistant organisms. This book considers how combination therapy can be applied in multiple situations, including cancer, HIV, tuberculosis, fungal infections, and more. Combination Therapy Against Multidrug Resistance gathers the most relevant information on the prospects of combination therapy as a strategy to combat multridrug resistance and helping to motivate the industrial sector and government agencies to invest more in research and development of this strategy as a weapon to tackle the multidrug resistance problem. It will be useful to academics and researchers involved in the development of new antimicrobial or antiinfective agents and treatment strtategies to combat multidrug resistance. Clinicians and medical nurses working in the field of infection prevention and control (IPC) will also find the book relevant - Explores strategic methods with investigation of both short- and long-term goals to combat multidrug resistance - Presents a broad scope to understand fully the ways to apply combined therapy to multidrug resistance - Provides an overview of combination therapy, but also includes specific cases such as cancer, tuberculosis, HIV and malaria

Genome Based Therapeutics

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Author : Institute of Medicine
language : en
Publisher: National Academies Press
Release Date : 2012-11-21

Genome Based Therapeutics written by Institute of Medicine and has been published by National Academies Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-11-21 with Medical categories.

The number of new drug approvals has remained reasonably steady for the past 50 years at around 20 to 30 per year, while at the same time the total spending on health-related research and development has tripled since 1990. There are many suspected causes for this trend, including increases in regulatory barriers, the rising costs of scientific inquiry, a decrease in research and development efficiency, the downstream effects of patient expirations on investment, and the lack of production models that have successfully incorporated new technology. Regardless, this trajectory is not economically sustainable for the businesses involved, and, in response, many companies are turning toward collaborative models of drug development, whether with other industrial firms, academia, or government. Introducing greater efficiency and knowledge into these new models and aligning incentives among participants may help to reverse the trends highlighted above, while producing more effective drugs in the process. Genome-Based Therapeutics explains that new technologies have the potential to open up avenues of development and to identify new drug targets to pursue. Specifically, improved validation of gene-disease associations through genomics research has the potential to revolutionize drug production and lower development costs. Genetic information has helped developers by increasing their understanding of the mechanisms of disease as well as individual patients' reactions to their medications. There is a need to identify the success factors for the various models that are being developed, whether they are industry-led, academia-led, or collaborations between the two. Genome-Based Therapeutics summarizes a workshop that was held on March 21, 2012, titled New Paradigms in Drug Discovery: How Genomic Data Are Being Used to Revolutionize the Drug Discovery and Development Process. At this workshop the goal was to examine the general approaches being used to apply successes achieved so far, and the challenges ahead.

Drug Target Identification Methods For Cryptosporidium

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Author : Ethan Benjamin Mattice
language : en
Publisher:
Release Date : 2024

Drug Target Identification Methods For Cryptosporidium written by Ethan Benjamin Mattice and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2024 with Cryptosporidiosis categories.

The intestinal protozoan parasite Cryptosporidium is a leading cause of diarrheal disease and is a significant burden worldwide. For healthy adults, disease is mild and self-limiting, however young children and the immunocompromised are those most heavily impacted. Unfortunately, the only FDA approved treatment is ineffective. Over the last decade and a half, many anticryptosporidial leads have been identified and studied extensively, however some have unknown drug targets. Surprisingly knowing a drug target isn't required for development, but understanding mechanism does provide benefits, one being a means to screen patients for potential drug-resistant parasites. Given the history of antimalarials, there is cause for concern for the rapid emergence of drug-resistant Cryptosporidium. One lead, MMV665917, was identified by screening the Medicines for Malaria Venture "Malaria Box" library of compounds. MMV665917 has been shown to be active against both C. parvum and C. hominis in vitro, and in various animal models providing ample information on dosing and toxicity. Development of this compound has led to a drug series with improved anticryptosporidial activity as well as mitigating toxicity and off target effects. Phenotypic assays have described the timing of MMV665917's activity in the parasite lifecycle and its impact on sexual differentiation. However, its target remains unknown, making it an ideal candidate for drug target identification studies. The focus of this work was on identifying the molecular target of MMV665917 utilizing a combination of forward and reverse genetics, transcriptomics, and proteomics. Drug resistance is an imperfect outcome for drug development, but also serves as a powerful tool for identifying drug targets. Research methods for Cryptosporidium are limited and in their infancy, requiring us to develop strategies to study drug resistance. Here, we have established a protocol for generating drug resistant C. parvum in a chronic mouse model. The method is reliant on a mutator strain of the parasite, CpMut, which is deficient in its proofreading ability. Using CpMut, we independently selected for two strains resistant to MMV665917, and using a backcrossing method show we can mate resistant and susceptible parasites to map mutations relevant to resistance. Whole genome sequencing of these resistant strains has provided several candidates to evaluate as potential MMV665917 targets. Using RNA-seq, we profiled changes in C. parvum's gene expression in response to exposure to various anticryptosporidials. Treatment with MMV665917, various analogs, and outgroup compounds revealed differential expression in Cryptosporidium's SUMOylation pathway specific to MMV665917 and its analogs. Using checkerboard assays, and inhibiting SUMOylation as well as treating with MMV665917 showed they act in synergy, suggesting SUMOylation is playing a role in C. parvum's compensatory response to MMV665917. These approaches have further characterized MMV665917, uncovered clues about its impact on parasite biology, and have directed us towards a potential drug target. Further evaluation is required to pin-point the mechanism of this compound. All together, we provide a framework for future drug target identification studies in Cryptosporidium, which will be a paramount aspect of future development of anticryptosporidials.

Can Pathway Based Approaches Overcome The Problems Of Target Based Drug Discovery

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Author : Allan B. Haberman
language : en
Publisher:
Release Date : 2006

Can Pathway Based Approaches Overcome The Problems Of Target Based Drug Discovery written by Allan B. Haberman and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006 with categories.

Combinative Strategy To Advance Target Based Anticryptosporidial Drug Discovery

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