scholarly journals Fishing for Nature’s Hits: Establishment of the Zebrafish as a Model for Screening Antidiabetic Natural Products

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Nadia Tabassum ◽  
Hongmei Tai ◽  
Da-Woon Jung ◽  
Darren R. Williams
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Danio Rerio ◽  
Morbidity Rate ◽  
Diabetes Research ◽  
Drug Candidates ◽  
Life Threatening ◽  
Screening Systems

Diabetes mellitus affects millions of people worldwide and significantly impacts their quality of life. Moreover, life threatening diseases, such as myocardial infarction, blindness, and renal disorders, increase the morbidity rate associated with diabetes. Various natural products from medicinal plants have shown potential as antidiabetes agents in cell-based screening systems. However, many of these potential “hits” fail in mammalian tests, due to issues such as poor pharmacokinetics and/or toxic side effects. To address this problem, the zebrafish (Danio rerio) model has been developed as a “bridge” to provide an experimentally convenient animal-based screening system to identify drug candidates that are activein vivo. In this review, we discuss the application of zebrafish to drug screening technologies for diabetes research. Specifically, the discovery of natural product-based antidiabetes compounds using zebrafish will be described. For example, it has recently been demonstrated that antidiabetic natural compounds can be identified in zebrafish using activity guided fractionation of crude plant extracts. Moreover, the development of fluorescent-tagged glucose bioprobes has allowed the screening of natural product-based modulators of glucose homeostasis in zebrafish. We hope that the discussion of these advances will illustrate the value and simplicity of establishing zebrafish-based assays for antidiabetic compounds in natural products-based laboratories.

scholarly journals Cryptosporidiosis: A Potential Anti-diarrheal Natural Product Drug Discovery Journey in Ghana, West Africa

2020 ◽  
pp. 85-93
Author(s):  
Senyo K. Botchie ◽  
Andrew G. Mtewa ◽  
Irene Ayi
Keyword(s):  
Developing Countries ◽  
Natural Products ◽  
Drug Discovery ◽  
Drug Development ◽  
Natural Product ◽  
Causative Organism ◽  
Drug Candidates ◽  
Cause Of Deaths

The overwhelming resistance to current drugs and the exhaustion of drug development interventions, as well as synthetic libraries, have compelled researchers to resort to the use of novel drug candidates derived from natural products. Cryptosporidium, the causative organism of Cryptosporidiosis, is no exception. The diarrhea-causing parasite is known to be the leading cause of deaths in children below age 5 in developing countries like Ghana and second to rotavirus as the causative agent for diarrhea in newborn calves and infants. Currently, the only FDA approved drug for the treatment of Cryptosporidiosis is Nitazoxanide. It is, therefore, needful to develop novel alternative candidates as it could aid in the decrease in child mortality and malnutrition in developing countries. Even though there have been significant limitations into anti-cryptosporidial drug development in vitro and in vivo, essential advancements are being made of which this article addresses the need for research into natural products. Some studies outlined in this paper has stated potential plant extracts showing anti-cryptosporidiosis efficacy. With the wealth of medicinal plant products and Cryptosporidium in vitro culture expertise available in our labs at Noguchi Memorial Institute for Medical research we are certain of making potential significant strides in the world of natural product Cryptosporidium drug discovery in Africa.

Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

2019 ◽  
Vol 4 (7) ◽  
Author(s):  
Samuel Egieyeh ◽  
Sarel F. Malan ◽  
Alan Christoffels
Keyword(s):  
Natural Products ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Structure Activity ◽  
Preclinical And Clinical Studies ◽  
Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

scholarly journals Defining desirable natural product derived anticancer drug space: optimization of molecular physicochemical properties and ADMET attributes

ADMET & DMPK ◽  
2016 ◽  
Vol 4 (2) ◽  
pp. 98 ◽  
Author(s):  
Deepika Singh
Keyword(s):  
Hydrogen Bond ◽  
Natural Products ◽  
Physicochemical Properties ◽  
Natural Product ◽  
Aqueous Solubility ◽  
Cancer Drug ◽  
Log P ◽  
Drug Candidates ◽  
Anti Cancer ◽  
Property Space

<p class="ADMETabstracttext">As part of our endeavor to enhance survival of natural product derived drug candidates and to guide the medicinal chemist to design higher probability space for success in the anti cancer drug development area, we embarked on a detailed study of the property space for a collection of natural product derived anti cancer molecules. We carried out a comprehensive analysis of properties for 24 natural products derived anti cancer drugs including clinical development candidates and a set of 27 natural products derived anti cancer lead compounds. In particular, we focused on understanding the interplay among eight physicochemical properties including like partition coefficient (log P), distribution coefficient at pH=7.4 (log D), topological polar surface area (TPSA), molecular weight (MW), aqueous solubility (log S), number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD) and number of rotatable bonds (n<sub>Rot</sub>) crucial for drug design and  relationships between physicochemical properties, ADME (absorption, distribution, metabolism, and elimination) attributes, and in silico toxicity profile for these two sets of compounds. This analysis provides guidance for the chemist to modify the existing natural product scaffold or designing of new anti cancer molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.</p>

scholarly journals Regulation of Antimycin Biosynthesis Is Controlled by the ClpXP Protease

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Bohdan Bilyk ◽  
Sora Kim ◽  
Asif Fazal ◽  
Tania A. Baker ◽  
Ryan F. Seipke
Keyword(s):  
Natural Products ◽  
Rna Polymerase ◽  
Natural Product ◽  
Morphological Differentiation ◽  
Dynamic Responses ◽  
Biosynthetic Pathways ◽  
Recognition Sequence ◽  
Σ Factor

ABSTRACT The survival of any microbe relies on its ability to respond to environmental change. Use of extracytoplasmic function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors, nearly all of which are uncharacterized, but those that have been characterized generally regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstituted in vitro ClpXP proteolysis of σAntA but not of a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntA in vivo was enhanced by removal of the ClpXP recognition sequence and that levels of the protein rose when cellular ClpXP protease activity was abolished. These data establish direct proteolysis as an alternative and, thus far, unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation. IMPORTANCE Natural products produced by Streptomyces species underpin many industrially and medically important compounds. However, the majority of the ∼30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. This unrevealed biochemical diversity is believed to comprise an untapped resource for natural product drug discovery. Major roadblocks preventing the exploitation of unexpressed biosynthetic pathways are a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time to our knowledge, and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.

scholarly journals Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1089-1094 ◽  
Author(s):  
Mark C. Walker ◽  
Benjamin W. Thuronyi ◽  
Louise K. Charkoudian ◽  
Brian Lowry ◽  
Chaitan Khosla ◽  
...  
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Polyketide Synthase ◽  
Building Blocks ◽  
Living Systems ◽  
Synthetic Compounds ◽  
Fluorinated Building Blocks

Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

scholarly journals Zebrafish as an Emerging Model for Bioassay-Guided Natural Product Drug Discovery for Neurological Disorders

Medicines ◽  
2019 ◽  
Vol 6 (2) ◽  
pp. 61 ◽  
Author(s):  
Arjun Pitchai ◽  
Rajesh Kannan Rajaretinam ◽  
Jennifer L. Freeman
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Neurological Disorders ◽  
Experimental Models ◽  
Bioactive Natural Products ◽  
Natural Product Research ◽  
Model Platform

Most neurodegenerative diseases are currently incurable, with large social and economic impacts. Recently, there has been renewed interest in investigating natural products in the modern drug discovery paradigm as novel, bioactive small molecules. Moreover, the discovery of potential therapies for neurological disorders is challenging and involves developing optimized animal models for drug screening. In contemporary biomedicine, the growing need to develop experimental models to obtain a detailed understanding of malady conditions and to portray pioneering treatments has resulted in the application of zebrafish to close the gap between in vitro and in vivo assays. Zebrafish in pharmacogenetics and neuropharmacology are rapidly becoming a widely used organism. Brain function, dysfunction, genetic, and pharmacological modulation considerations are enhanced by both larval and adult zebrafish. Bioassay-guided identification of natural products using zebrafish presents as an attractive strategy for generating new lead compounds. Here, we see evidence that the zebrafish’s central nervous system is suitable for modeling human neurological disease and we review and evaluate natural product research using zebrafish as a vertebrate model platform to systematically identify bioactive natural products. Finally, we review recently developed zebrafish models of neurological disorders that have the potential to be applied in this field of research.

scholarly journals A GenoChemetic strategy for derivatization of the violacein natural product scaffold

2017 ◽  
Author(s):  
Hung-En Lai ◽  
Alan M. C. Obled ◽  
Soo Mei Chee ◽  
Rhodri M. Morgan ◽  
Rosemary Lynch ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Space ◽  
Coupling Reaction ◽  
Biosynthesis Pathway ◽  
Proof Of Concept ◽  
Substrate Analogues ◽  
Cross Coupling Reaction ◽  
Wide Range

AbstractNatural products and their analogues are often challenging to synthesise due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with eight tryptophan substrate analogues or tryptophan halogenase RebH in vivo, 68 new-to-nature analogues of violacein were generated, demonstrating extraordinary promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from brominated violacein analogues via Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein, we demonstrate a flexible and rapid approach to access diverse chemical space that can be applied to a wide range of natural product scaffolds.

Cheminformatics techniques in antimalarial drug discovery and development from natural products 2: Molecular scaffold and machine learning approaches

2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Samuel Egieyeh ◽  
Sarel F. Malan ◽  
Alan Christoffels
Keyword(s):  
Machine Learning ◽  
Natural Products ◽  
Predictive Modeling ◽  
Antimalarial Drug ◽  
Learning Approaches ◽  
Molecular Scaffold ◽  
Drug Discovery And Development ◽  
Drug Candidates

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in-vitro antiplasmodial activities. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of two cheminformatics techniques (including molecular scaffold analysis and bioactivity predictive modeling via Machine learning) to natural products with in-vitro and in-vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

Natural product inhibitors of cyclooxygenase (COX) enzyme: A Review on Current status and future perspectives

2020 ◽  
Vol 27 ◽  
Author(s):  
Goutami Ambati G ◽  
Sanjay M. Jachak
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Current Status ◽  
Marine Origin ◽  
Cox Inhibitors ◽  
Potential Source ◽  
Cox 2 ◽  
Inhibition Property

Background: Several clinically used COX-1 and COX-2 inhibitor drugs were reported to possess severe side effects like GI ulcers and cardiovascular disturbances, respectively. Natural products being structurally diverse always attracted the attention of chemists/medicinal chemists as a potential source of lead molecules in drug discovery process. COX-2 inhibitory natural products also possess potential cancer chemopreventive property against various cancers including that of colon, breast, and prostate. Methods: Various in vitro, in vivo, in silico standardized methods were used to evaluate COX inhibition property of different secondary metabolites isolated from plant, microbial and marine origin. Results: We had earlier reported a detailed account of natural product inhibitors of COX reported during 1995-2005 in 2006. In the proposed review we report 158 natural product inhibitors of COX during 2006 to 2019 belonging to various secondary metabolite classes such as alkaloids, terpenoids, polyphenols as flavonoids, chromones, coumarins, lignans, anthraquinones, naphthalenes, curcuminoids, diarylheptanoids and miscellaneous compounds of plant and marine origin. Further structure activity relationship (SAR) studies of possible leads are also included in the article. Conclusion: COX inhibitors served as a potential source of lead molecules for discovery and development of anti-inflammatory drugs. Compilation of natural product and semi-synthetic inhibitors of COX may serve as valuable information to the researchers who are looking for possible lead molecules from natural source to conduct further preclinical and clinical studies.

Manipulating nature's sugar biosynthetic machineries for glycodiversification of macrolides: Recent advances and future prospects

2007 ◽  
Vol 79 (4) ◽  
pp. 785-799 ◽  
Author(s):  
Christopher J. Thibodeaux ◽  
Hung-wen Liu
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Biosynthetic Pathway ◽  
Effective Means ◽  
Future Prospects ◽  
Research Groups ◽  
Targeted Disruption ◽  
In Vitro Methods

Changing the sugar structures and glycosylation patterns of natural products is an effective means of altering the biological activity of clinically useful drugs. Several recent strategies have provided researchers with the opportunity to manipulate sugar structures and to change the sugar moieties attached to these natural products via a biosynthetic approach. In this review, we explore the utility of contemporary in vivo and in vitro methods to achieve natural product glycodiversification. This study will focus on recent progress from our laboratory in elucidating the biosynthesis of D-desosamine, a deoxysugar component of many macrolide antibiotics, and will highlight how we have engineered the D-desosamine biosynthetic pathway in Streptomyces venezuelae through targeted disruption and heterologous expression of the sugar biosynthetic genes to generate a variety of new glycoforms. The in vitro exploitation of the substrate flexibility of the endogenous D-desosamine glycosyltransferase (GT) to generate many non-natural glycoforms will also be discussed. These experiments are compared with recent work from other research groups on the same topics. Finally, the significance of these studies for the future prospects of natural product glycodiversification is discussed.

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