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Journal of Industrial Microbiology &... Dec 2021Microbial genome mining for drug discovery and development has been accelerating in recent years, driven by technical advancements in genome sequencing, bioinformatics,... (Review)
Review
Microbial genome mining for drug discovery and development has been accelerating in recent years, driven by technical advancements in genome sequencing, bioinformatics, metabolomics/metabologenomics, and synthetic biology. Microbial genome mining is a multistep process that starts with the sequencing of microbes that encode multiple secondary metabolites and identifying new and novel secondary metabolite biosynthetic gene clusters (BGCs) to pursue. The initial steps in the process are critical for the overall success, and they encompass the most innovative new technologies to revitalize natural product discovery. As microbial genome mining has matured in recent years, unvalidated conjectures about what microbes to pursue, how to identify legitimate secondary metabolite BGCs, and how to sequence DNA to satisfactory levels of completion have been identified. The solutions to correct the misconceptions around these topics are beginning to be implemented.
Topics: Biological Products; Computational Biology; Drug Discovery; Genome, Bacterial; Multigene Family
PubMed: 34279640
DOI: 10.1093/jimb/kuab044 -
Clinical and Experimental Rheumatology 2016The Corrona US national registry collects data concerning patient status from both the rheumatologist and patient at routine clinical encounters. Corrona has functioning... (Review)
Review
The Corrona US national registry collects data concerning patient status from both the rheumatologist and patient at routine clinical encounters. Corrona has functioning disease registries in rheumatoid arthritis, psoriatic arthritis, spondyloarthropathies, psoriasis and inflammatory bowel disease. Corrona merges data concerning long-term effectiveness and safety, as well as comparative and cost effectiveness of agents to treat these autoimmune diseases.
Topics: Antirheumatic Agents; Autoimmune Diseases; Biological Products; Cost-Benefit Analysis; Drug Costs; Humans; Registries; Rheumatic Diseases; Rheumatology; Time Factors; Treatment Outcome; United States
PubMed: 27762197
DOI: No ID Found -
The Journal of Allergy and Clinical... Sep 2023Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with...
Impact of Initiating Biologics in Patients With Severe Asthma on Long-Term Oral Corticosteroids or Frequent Rescue Steroids (GLITTER): Data From the International Severe Asthma Registry.
BACKGROUND
Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with HOCS alone.
OBJECTIVE
To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS.
METHODS
This was a propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry. Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCSs for ≥1 year or ≥4 courses of rescue OCSs within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with noninitiators. The impact of biologic initiation on asthma outcomes was assessed using generalized linear models.
RESULTS
We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations per year versus noninitiators (0.64 vs 2.06; rate ratio, 0.27 [95% CI, 0.10-0.71]). Biologic initiators were 2.2 times more likely than noninitiators to take a daily long-term OCS dose of less than 5 mg (risk probability, 49.6% vs 22.5%; P = .002) and had a lower risk of asthma-related emergency department visits (relative risk, 0.35 [95% CI, 0.21-0.58]; rate ratio, 0.26 [0.14-0.48]) and hospitalizations (relative risk, 0.31 [95% CI, 0.18-0.52]; rate ratio, 0.25 [0.13-0.48]).
CONCLUSIONS
In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and health care resource utilization.
Topics: Adult; Humans; Prospective Studies; Asthma; Adrenal Cortex Hormones; Steroids; Biological Products; Anti-Asthmatic Agents
PubMed: 37301430
DOI: 10.1016/j.jaip.2023.05.044 -
Marine Drugs Dec 2022Cyanobacteria ascribed to the genus (Family Oscillatoriaceae) represent a potential therapeutic gold mine of chemically and biologically diverse natural products that... (Review)
Review
Cyanobacteria ascribed to the genus (Family Oscillatoriaceae) represent a potential therapeutic gold mine of chemically and biologically diverse natural products that exhibit a wide array of biological properties. Phylogenetic analyses have established the 'morpho-type' as a highly polyphyletic group and have resulted in taxonomic revision and description of an additional six new cyanobacterial genera in the same family to date. Among the most prolific marine cyanobacterial producers of biologically active compounds are the species (previously then ) (previously ), and . Over the years, compounding evidence from in vitro and in vivo studies in support of the significant pharmaceutical potential of ''-derived natural products has made the morphotype a significant target for biomedical research and novel drug leads development. This comprehensive review covers compounds with reported anti-infective activities through 2022 from the morphotype, including new genera arising from recent phylogenetic re-classification. So far, 72 anti-infective secondary metabolites have been isolated from various , , , and species. These compounds showed significant antibacterial, antiparasitic, antifungal, antiviral and molluscicidal effects. Herein, a comprehensive literature review covering the natural source, chemical structure, and biological/pharmacological properties will be presented.
Topics: Lyngbya; Phylogeny; Cyanobacteria; Biological Products; Lyngbya Toxins
PubMed: 36547915
DOI: 10.3390/md20120768 -
Accounts of Chemical Research Mar 2015In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on "Frontiers in Organic Synthesis". This...
In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on "Frontiers in Organic Synthesis". This Accounts of Chemical Research thematic issue on "Synthesis, Design, and Molecular Function" is intended to provide further perspective now from well into the 21st century. Much has happened in the past few decades. The targets, methods, strategies, reagents, procedures, goals, funding, practices, and practitioners of synthesis have changed, some in dramatic ways as documented in impressive contributions to this issue. However, a constant for most synthesis studies continues to be the goal of achieving function with synthetic economy. Whether in the form of new catalysts, reagents, therapeutic leads, diagnostics, drug delivery systems, imaging agents, sensors, materials, energy generation and storage systems, bioremediation strategies, or molecules that challenge old theories or test new ones, the function of a target has been and continues to be a major and compelling justification for its synthesis. While the targets of synthesis have historically been heavily represented by natural products, increasingly design, often inspired by natural structures, is providing a new source of target structures exhibiting new or natural functions and new or natural synthetic challenges. Complementing isolation and screening approaches to new target identification, design enables one to create targets de novo with an emphasis on sought-after function and synthetic innovation with step-economy. Design provides choice. It allows one to determine how close a synthesis will come to the ideal synthesis and how close a structure will come to the ideal function. In this Account, we address studies in our laboratory on function-oriented synthesis (FOS), a strategy to achieve function by design and with synthetic economy. By starting with function rather than structure, FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion. Reported herein are examples of FOS associated with (a) molecular recognition, leading to the first designed phorbol-inspired protein kinase C regulatory ligands, the first designed bryostatin analogs, the newest bryologs, and a new family of designed kinase inhibitors, (b) target modification, leading to highly simplified but functionally competent photonucleases-molecules that cleave DNA upon photoactivation, (c) drug delivery, leading to cell penetrating molecular transporters, molecules that ferry other attached or complexed molecules across biological barriers, and (d) new reactivity-regenerating reagents in the form of functional equivalents of butatrienes, reagents that allow for back-to-back three-component cycloaddition reactions, thus achieving structural complexity and value with step-economy. While retrosynthetic analysis seeks to identify the best way to make a target, retrofunction analysis seeks to identify the best targets to make. In essence, form (structure) follows function.
Topics: Animals; Biological Products; Bryostatins; DNA Cleavage; Drug Delivery Systems; Drug Design; Humans; Ligands; Organic Chemicals; Protein Kinase C; Protein Kinase Inhibitors
PubMed: 25742599
DOI: 10.1021/acs.accounts.5b00004 -
Annual Review of Biochemistry 2009Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a... (Review)
Review
Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lie behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin (PT), and the clinical candidate for treatment of malaria FR-900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations, and a wealth of new biochemistry has been revealed through their study. These investigations have also suggested new strategies for natural product discovery.
Topics: Animals; Biological Products; Biosynthetic Pathways; Drug Therapy; Herbicides; Organophosphonates; Phosphinic Acids; Phospholipids; Polysaccharides
PubMed: 19489722
DOI: 10.1146/annurev.biochem.78.091707.100215 -
Fungal Genetics and Biology : FG & B Apr 2016Fungal natural products possess biological activities that are of great value to medicine, agriculture and manufacturing. Recent metagenomic studies accentuate the... (Review)
Review
Fungal natural products possess biological activities that are of great value to medicine, agriculture and manufacturing. Recent metagenomic studies accentuate the vastness of fungal taxonomic diversity, and the accompanying specialized metabolic diversity offers a great and still largely untapped resource for natural product discovery. Although fungal natural products show an impressive variation in chemical structures and biological activities, their biosynthetic pathways share a number of key characteristics. First, genes encoding successive steps of a biosynthetic pathway tend to be located adjacently on the chromosome in biosynthetic gene clusters (BGCs). Second, these BGCs are often are located on specific regions of the genome and show a discontinuous distribution among evolutionarily related species and isolates. Third, the same enzyme (super)families are often involved in the production of widely different compounds. Fourth, genes that function in the same pathway are often co-regulated, and therefore co-expressed across various growth conditions. In this mini-review, we describe how these partly interlinked characteristics can be exploited to computationally identify BGCs in fungal genomes and to connect them to their products. Particular attention will be given to novel algorithms to identify unusual classes of BGCs, as well as integrative pan-genomic approaches that use a combination of genomic and metabolomic data for parallelized natural product discovery across multiple strains. Such novel technologies will not only expedite the natural product discovery process, but will also allow the assembly of a high-quality toolbox for the re-design or even de novo design of biosynthetic pathways using synthetic biology approaches.
Topics: Biological Products; Biosynthetic Pathways; Computational Biology; Fungi; Genetic Engineering; Genome, Fungal; Genomics; Multigene Family
PubMed: 26775250
DOI: 10.1016/j.fgb.2016.01.006 -
World Journal of Gastroenterology Mar 2017Biologic therapy, such as those that target tumor necrosis factor (TNF) signaling, has proven to be an efficacious method of treatment for patients with inflammatory... (Review)
Review
Biologic therapy, such as those that target tumor necrosis factor (TNF) signaling, has proven to be an efficacious method of treatment for patients with inflammatory bowel disease (IBD) with regards to symptom management and mucosal healing. However, the rising prevalence of IBD worldwide and the ever-increasing burden of biologic pharmaceuticals in the health care industry is alarming for insurance companies, clinicians, and patients. The impending patent expiry and the relatively high costs of biologics, particularly anti-TNF agents, have paved the way for biosimilar development for IBD. The United States Food and Drug Administration defines a biosimilar as a biological product that is highly similar to its reference medicinal product, with no clinically meaningful differences in terms of safety, purity, and potency. The hope with biosimilars is that their entry into the market will be able to drive competition between pharmaceutical companies to reduce prices like that of the generic market, and that access to appropriate biologic treatments for IBD patients is increased in the long-term. Yet, there are challenging issues such as indication extrapolation and interchangeability that are still being debated in the field of IBD and must be addressed in future issued guidance. This review will discuss the issues and implications concerning the use of biosimilar therapy for IBD.
Topics: Antibodies, Monoclonal; Biological Products; Biosimilar Pharmaceuticals; Drug Substitution; Humans; Inflammatory Bowel Diseases; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 28373759
DOI: 10.3748/wjg.v23.i11.1932 -
Marine Drugs Jun 2022Large-scale genome-mining analyses have identified an enormous number of cryptic biosynthetic gene clusters (BGCs) as a great source of novel bioactive natural products.... (Review)
Review
Large-scale genome-mining analyses have identified an enormous number of cryptic biosynthetic gene clusters (BGCs) as a great source of novel bioactive natural products. Given the sheer number of natural product (NP) candidates, effective strategies and computational methods are keys to choosing appropriate BGCs for further NP characterization and production. This review discusses genomics-based approaches for prioritizing candidate BGCs extracted from large-scale genomic data, by highlighting studies that have successfully produced compounds with high chemical novelty, novel biosynthesis pathway, and potent bioactivities. We group these studies based on their BGC-prioritization logics: detecting presence of resistance genes, use of phylogenomics analysis as a guide, and targeting for specific chemical structures. We also briefly comment on the different bioinformatics tools used in the field and examine practical considerations when employing a large-scale genome mining study.
Topics: Biological Products; Biosynthetic Pathways; Computational Biology; Genome, Bacterial; Genomics; Multigene Family
PubMed: 35736201
DOI: 10.3390/md20060398 -
Oxidative Medicine and Cellular... 2013Reactive oxygen species (ROS) are cellular signals generated ubiquitously by all mammalian cells, but their relative unbalance triggers also diseases through... (Review)
Review
Reactive oxygen species (ROS) are cellular signals generated ubiquitously by all mammalian cells, but their relative unbalance triggers also diseases through intracellular damage to DNA, RNA, proteins, and lipids. NADPH oxidases (NOX) are the only known enzyme family with the sole function to produce ROS. The NOX physiological functions concern host defence, cellular signaling, regulation of gene expression, and cell differentiation. On the other hand, increased NOX activity contributes to a wide range of pathological processes, including cardiovascular diseases, neurodegeneration, organ failure, and cancer. Therefore targeting these enzymatic ROS sources by natural compounds, without affecting the physiological redox state, may be an important tool. This review summarizes the current state of knowledge of the role of NOX enzymes in physiology and pathology and provides an overview of the currently available NADPH oxidase inhibitors derived from natural extracts such as polyphenols.
Topics: Animals; Antioxidants; Biological Products; Cells; Disease; Humans; NADPH Oxidases; Reactive Oxygen Species
PubMed: 24381714
DOI: 10.1155/2013/271602