scholarly journals Mechanisms of Action of Ribosomally Synthesized and Posttranslationally Modified Peptides (RiPPs)

2021 ◽  
Author(s):  
Li Cao ◽  
Truc Do ◽  
A James Link
Keyword(s):  
Natural Products ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Structural Information ◽  
Genome Mining ◽  
Mechanisms Of Action ◽  
Detailed Mechanism ◽  
Modified Peptides ◽  
Drug Leads

Abstract Natural products remain a critical source of medicines and drug leads. One of the most rapidly growing superclasses of natural products is RiPPs: ribosomally synthesized and posttranslationally modified peptides. RiPPs have rich and diverse bioactivities. This review highlights examples of the molecular mechanisms of action that underly those bioactivities. Particular emphasis is placed on RiPP/target interactions for which there is structural information. This detailed mechanism of action work is critical toward the development of RiPPs as therapeutics and can also be used to prioritize hits in RiPP genome mining studies.

scholarly journals Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2542
Author(s):  
Linda Sukmarini
Keyword(s):  
Natural Products ◽  
Genome Mining ◽  
Screening Methods ◽  
Technological Advancement ◽  
Natural Origin ◽  
Drug Discovery And Development ◽  
New Methodologies ◽  
Analytical Instrumentation ◽  
Microbial Natural Products ◽  
Drug Leads

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.

scholarly journals Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

2019 ◽  
pp. 1-12 ◽  
Author(s):  
A.S. V. Prasad
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Organic Anion ◽  
Density Lipoprotein ◽  
The United States ◽  
Mechanisms Of Action ◽  
Lipid Lowering ◽  
Intervention Trial ◽  
Ligand Interaction ◽  
Cholesterol Acyl Transferase

Fibrates are a class of medication that mainly lowers the blood triglyceride levels. They reduce the LDL and increase the levels of HDL C, in the blood. Clofibrate, the first member to be discovered  in 1962 , and introduced in USA in 1967, is withdrawn in 2002, due to unexplained hepatomegaly, hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early 1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome,  macrovascular and microvascular diabetic complications  like stroke, myocardial infarction, peripheral vascular disease  and  diabetic  retinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) ,  FIELD trail.  (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,   ACCORD -Lipid trial  (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and  BIP (Bezafibrate Infarction Prevention Study)  trial and angiography trials, like LOCAT (Lopid Coronary Angiography Trial)  and BECLAIT (Bezafibrate Coronary Atherosclerosis Intervention Trial) demonstrated the  beneficial effects of gemfibrozil and fenofibrate.  Their mechanism of action remained obscure for three decades, ie till 1990s, when their mode of action was found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)  modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involving  the various  enzymes like LCAT (Lecithin-cholesterol acyl transferase)  and CYP7A1 etc.  (cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) ) ,  transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP, OATP (Na+-dependent taurocholate transporter / organic anion transporters) . These are the.) and nuclear factors like LXR, PPAR alfa etc. (liver orphan receptor α , and peroxisome proliferative nuclear factor) , in relation to the mechanisms  of action of fibrates are discussed . Areas of current interests in literature are briefed.

Molecule which changed the view on skin treatment

2021 ◽  
pp. 44-55
Author(s):  
L.Ya. Fedorich
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Local Treatment ◽  
Mechanisms Of Action ◽  
Clinical Effects ◽  
Topical Retinoids ◽  
Acne Therapy ◽  
Universal Mechanism

Objective — to study the modern classification, mechanisms of action and clinical effects of vitamin A derivatives, to analyze retinoid for local treatment of various dermatoses with a universal mechanism of action at the epidermis and dermis levels. Materials and methods. A review of the literature and an analysis of the results of international clinical trials of drugs based on the natural retinoid of the first generation — tretinoin (retinoic acid) is presented. The works of dozens of authors since 1980s to the present day are analyzed. Most sources provide detailed information on the results of topical retinoids in acne therapy, which are the base of clinical guidelines. Long-term (6 months or more) studies of retinoic acid-based preparations carried out in recent decades have discovered the unique clinical effects of tretinoin in the treatment of skin photoaging, actinic keratosis, etc. They are achieved due to the effect of tretinoid on the nuclear receptors of keratinocytes and fibroblasts. Results and discussion. The molecular mechanisms of action of retinoic acid, realizing the cellular and tissue effects of the most studied retinoid, are systematized and grouped in a single review. It has been proven that a unique feature of tretinin is its ability to activate directly all subtypes of RARs- and, indirectly, RARs-nuclear receptors of skin cells. A new modern drug for external use is presented — AltrenoТМ lotion containing micronized 0.05 % tretinoin in combination with sodium hyaluronate, soluble collagen and glycerin. This combination exhibits the expected clinical efficacy in acne therapy and prevents side effects such as dryness, redness and exfoliation. AltrenoТМ is approved for use in children of 9 years of age and older. Conclusions. Tretinoin (retinoic acid) is a modern powerful retinoid with a universal mechanism of action, recommended for the treatment of acne.

scholarly journals Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes

2016 ◽  
Vol 113 (13) ◽  
pp. 3521-3526 ◽  
Author(s):  
Wei Ding ◽  
Wan-Qiu Liu ◽  
Youli Jia ◽  
Yongzhen Li ◽  
Wilfred A. van der Donk ◽  
...  
Keyword(s):  
Natural Products ◽  
Biological Activities ◽  
Genome Mining ◽  
Substrate Specificities ◽  
Modified Peptides ◽  
Fungal Natural Products ◽  
Different Strains

Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as an S-adenosylmethionine–dependent α-N-methyltransferase that converts phomopsin A to anN,N-dimethylated congener (phomopsin E), and show that the methyltransferases involved in dikaritin biosynthesis have evolved differently and likely have broad substrate specificities. Genome mining studies identified eight previously unknown dikaritins in different strains, highlighting the untapped capacity of RiPP biosynthesis in fungi and setting the stage for investigating the biological activities and unknown biosynthetic transformations of this family of fungal natural products.

scholarly journals Exploring the Molecular Mechanisms of Action of Samoan Medicinal Plants via Chemical Genetic Analyses

2021 ◽  
Author(s):  
◽  
Seeseei Molimau-Samasoni
Keyword(s):  
Natural Products ◽  
Medicinal Plants ◽  
Medicinal Plant ◽  
Aqueous Extract ◽  
Mechanism Of Action ◽  
Condensed Tannin ◽  
Iron Chelation ◽  
Yeast Cells ◽  
Intracellular Iron ◽  
Drug Leads

<p>Natural products are a robust source of drug leads, and medicinal plants have been the source of natural products that are important pharmaceuticals in modern medicine. Samoan medicinal plants have been investigated in the past, but their potential as a source of new drug leads has not been realized. I hypothesized that determining the mechanism of action of Samoan medicinal plant extracts would provide insight into their pharmaceutical potential. The work described herein was carried out on 11 Samoan medicinal plants, from which 22 extracts were prepared. A bioactivity rate of 68% was determined when 15 of the 22 extracts inhibited the growth of yeast (Saccharomyces cerevisiae). The medicinal plant Psychotria insularum was the most potent, thus genome-wide analyses were completed using the haploid deletion mutant library of S. cerevisiae. Yeast strains deficient in iron transport were hypersensitive to the P. insularum aqueous extract. Further investigations showed that exogenous iron supplementation rescued the growth defect induced by P. insularum extracts, suggesting that P. insularum reduced intracellular iron. Fittingly, yeast cells treated with P. insularum extracts contained less intracellular iron than control cells. Paraxodically, the expression levels of iron transporter proteins were upregulated upon extract treatment. When we investigated iron-requiring cellular processes, we found that yeast cells treated with P. insularum extracts exhibited a respiratory deficient phenotype and reduced heme synthesis, indicative of an impaired cellular iron status. These findings suggested that P. insularum reduced bioavailable iron leading to the induction of the low iron response, and indeed the extracts of P. insularum were shown to chelate iron via the iron-chelating CAS assay. To translate results from yeast to mammalian cells, we treated primary murine macrophages with P. insularum extracts and detected an anti-inflammatory response, which we found to correlate with reduced activity of the iron-requiring aconitase enzyme. We further determined using pooled diploid mutant genetic analyses that the extracts of P. insularum did not have a genetic target. To identify the compound mediating the iron chelation mechanism, bioassay-guided isolation was conducted. Fractionation of the crude aqueous extract of P. insularum produced a relatively pure fraction that NMR and the acid-butanol assay identified as a condensed tannin. Together, these results indicate a relationship between iron chelation, a condensed tannin and inflammation. Further, we established an iron chelation mechanism of action by which P. insularum extracts are used to treat inflammation-associated symptoms in traditional Samoan medicine. Lastly, the findings presented here substantiate the reliability of plants with ethnobotanical background as sources for bioactive natural products.</p>

scholarly journals Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived Streptomyces sp. IB201691-2A

2020 ◽  
Vol 8 (5) ◽  
pp. 680
Author(s):  
Irina Voitsekhovskaia ◽  
Constanze Paulus ◽  
Charlotte Dahlem ◽  
Yuriy Rebets ◽  
Suvd Nadmid ◽  
...  
Keyword(s):  
Natural Products ◽  
Lake Baikal ◽  
Structure Elucidation ◽  
Genome Mining ◽  
Ecological Niches ◽  
Hydroxyl Groups ◽  
Streptomyces Sp ◽  
Drug Leads ◽  
Promising Source ◽  
Antiproliferative Activities

Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis. In the course of an activity guided screening three new angucyclines, named baikalomycins A–C, were isolated and characterized, highlighting the potential of poorly investigated ecological niches. Besides that, the strain was found to accumulate large quantities of rabelomycin and 5-hydroxy-rabelomycin, known shunt products in angucyclines biosynthesis. Baikalomycins A–C demonstrated varying degrees of anticancer activity. Rabelomycin and 5-hydroxy-rabelomycin further demonstrated antiproliferative activities. The structure elucidation showed that baikalomycin A is a modified aquayamycin with β-d-amicetose and two additional hydroxyl groups at unusual positions (6a and 12a) of aglycone. Baikalomycins B and C have alternating second sugars attached, α-l-amicetose and α-l-aculose, respectively. The gene cluster for baikalomycins biosynthesis was identified by genome mining, cloned using a transformation-associated recombination technique and successfully expressed in S. albus J1074. It contains a typical set of genes responsible for an angucycline core assembly, all necessary genes for the deoxy sugars biosynthesis, and three genes coding for the glycosyltransferase enzymes. Heterologous expression and deletion experiments allowed to assign the function of glycosyltransferases involved in the decoration of baikalomycins aglycone.

scholarly journals Towards the production of tikitericin: A novel peptide from Thermogemmatispora strain T81

2021 ◽  
Author(s):  
◽  
Benjamin Baker
Keyword(s):  
Antimicrobial Activity ◽  
Natural Products ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Genome Mining ◽  
New Drugs ◽  
Taupo Volcanic Zone ◽  
Ms Imaging ◽  
Modified Peptides ◽  
Microbial Natural Products

<p>The utilisation of natural products for treatment of human ailments has been rooted in various cultures for centuries. Extraction of natural products has been essential for the discovery of new drugs and inspiration for synthetic analogues. Since the success of penicillin, microbial natural products have been of interest. Genome mining of Thermogemmatisporastrain T81, a thermophile from the Taupo Volcanic Zone, found the potential for the production of novel ribosomally synthesised and post-translationally modified peptides (RiPPs). Previous work showed that T81 exhibited antimicrobial activity against a wide variety of extremophillic bacteria. Although the three thiopeptides encoded forin the genome of T81 have not been found, the lanthipeptide tikitericin has recently been isolated and described. Unfortunately tikitericin is produced in low quantities by T81 andbioactivity data has not yet been obtained. Because of its potential antimicrobial activity, different routes to produce it are of interest. The aim of this project wasto synthesisetikitericin by solid phase peptide synthesis. MS imaging was also utilised to search for the presence of tikitericin as an antimicrobial agent in situ.</p>

scholarly journals Radical SAM Enzymes and Ribosomally‐Synthesized and Post‐translationally Modified Peptides: A Growing Importance in the Microbiomes

2021 ◽  
Vol 9 ◽  
Author(s):  
Alhosna Benjdia ◽  
Olivier Berteau
Keyword(s):  
Natural Products ◽  
Posttranslational Modifications ◽  
High Throughput Screening ◽  
Combinatorial Libraries ◽  
Special Focus ◽  
Radical Sam ◽  
Radical Sam Enzymes ◽  
Recent Developments ◽  
Modified Peptides ◽  
Drug Leads

To face the current antibiotic resistance crisis, novel strategies are urgently required. Indeed, in the last 30 years, despite considerable efforts involving notably high-throughput screening and combinatorial libraries, only few antibiotics have been launched to the market. Natural products have markedly contributed to the discovery of novel antibiotics, chemistry and drug leads, with more than half anti-infective and anticancer drugs approved by the FDA being of natural origin or inspired by natural products. Among them, thanks to their modular structure and simple biosynthetic logic, ribosomally synthesized and posttranslationally modified peptides (RiPPs) are promising scaffolds. In addition, recent studies have highlighted the pivotal role of RiPPs in the human microbiota which remains an untapped source of natural products. In this review, we report on recent developments in radical SAM enzymology and how these unique biocatalysts have been shown to install complex and sometimes unprecedented posttranslational modifications in RiPPs with a special focus on microbiome derived enzymes.

Mechanisms of Action of Different Drugs of Abuse

2014 ◽  
Author(s):  
Lindsay M. McCracken ◽  
Mandy L. McCracken ◽  
R. Adron Harris
Keyword(s):  
Drug Use ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Chronic Administration ◽  
Repeated Administration ◽  
Mechanisms Of Action ◽  
Neuronal Membrane ◽  
Sedative Hypnotics ◽  
Routes Of Drug Administration

Drugs of abuse represent a spectrum of chemically diverse compounds that are used via various routes of drug administration depending on the drug and its preparation. Although the exact molecular mechanisms by which these agents act to produce their intoxicating effects are not completely understood, many drugs of abuse are known to bind to specific neuronal membrane proteins that produce effects on cellular signaling and ultimately on behavior. With repeated administration of a drug, individuals often develop tolerance, and discontinuation of drug use following chronic administration typically results in withdrawal symptoms. This chapter describes the mechanism of action for the following classes of drugs of abuse: alcohol, cannabinoids, hallucinogens, inhalants, nicotine, opioids, sedative hypnotics, and stimulants. In addition, mechanisms of tolerance and withdrawal are discussed.

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