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 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.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development

2019 ◽  
Vol 25 (39) ◽  
pp. 5395-5431 ◽  
Author(s):  
Fahmida Alam ◽  
Md. Asiful Islam ◽  
Mohammad Amjad Kamal ◽  
Siew Hua Gan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Natural Products ◽  
Drug Discovery ◽  
Drug Development ◽  
Discovery Process ◽  
Drug Discovery Process

Over the years, natural products have shown success as antidiabetics in in vitro, in vivo studies and clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs, and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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 Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Justus Amuche Nweze ◽  
Florence N. Mbaoji ◽  
Yan-Ming Li ◽  
Li-Yan Yang ◽  
Shu-Shi Huang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Neglected Tropical Diseases ◽  
Marine Organisms ◽  
New Drugs ◽  
Screening Methods ◽  
Pharmaceutical Industries

Abstract Background Malaria and neglected communicable protozoa parasitic diseases, such as leishmaniasis, and trypanosomiasis, are among the otherwise called diseases for neglected communities, which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa, Asia, and the Americas. Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period, which have encouraged resistance. These have prompted many researchers to focus on finding new drugs that are safe, effective, and affordable from marine environments. The aim of this review was to show the diversity, structural scaffolds, in-vitro or in-vivo efficacy, and recent progress made in the discovery/isolation of marine natural products (MNPs) with potent bioactivity against malaria, leishmaniasis, and trypanosomiasis. Main text We searched PubMed and Google scholar using Boolean Operators (AND, OR, and NOT) and the combination of related terms for articles on marine natural products (MNPs) discovery published only in English language from January 2016 to June 2020. Twenty nine articles reported the isolation, identification and antiparasitic activity of the isolated compounds from marine environment. A total of 125 compounds were reported to have been isolated, out of which 45 were newly isolated compounds. These compounds were all isolated from bacteria, a fungus, sponges, algae, a bryozoan, cnidarians and soft corals. In recent years, great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds. Comparably, some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs. However, very few of these MNPs have a pharmaceutical destiny due to lack of the following: sustainable production of the bioactive compounds, standard efficient screening methods, knowledge of the mechanism of action, partnerships between researchers and pharmaceutical industries. Conclusions It is crystal clear that marine organisms are a rich source of antiparasitic compounds, such as alkaloids, terpenoids, peptides, polyketides, terpene, coumarins, steroids, fatty acid derivatives, and lactones. The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

scholarly journals 1341. Development of a Series of High-Throughput Screens to Identify Leads for Nontuberculous Mycobacteria Drug Design

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S485-S485
Author(s):  
Sarah McGuffin ◽  
Steven Mullen ◽  
Julie Early ◽  
Tanya Parish
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
High Throughput ◽  
Nontuberculous Mycobacteria ◽  
Human Infection ◽  
Attrition Rate ◽  
In Vitro Assays ◽  
Vitro Assay

Abstract Background Nontuberculous mycobacteria (NTM), particularly Mycobacterium avium complex and Mycobacterium abscessus complex, cause significant morbidity and mortality in patients with impaired host immunity or pre-existing structural lung conditions. NTM infections are increasing at an alarming rate worldwide and there is a dearth of progress in regard to the development of efficacious and tolerable drugs to treat such infections. Traditional drug discovery screens do not account for the diverse physiological conditions, microenvironments, and compartments that the bacilli encounter during human infection. In order to help populate the NTM drug pipeline, and explore the disconnect between in vitro activity, in vivo activity, and clinical outcomes, we are developing a high throughput in vitro assay platform that will more closely model the unique infection-relevant conditions encountered by NTM. Methods We are developing and validating a suite of in vitro assays that screen compounds for activity against extracellular planktonic bacteria, extracellular bacteria within biofilms, intracellular bacteria, and nutrient-starved non-replicating bacteria. Results We are using both the smooth and rough morphotypes of M. abscessus and M. avium. We have validated high throughput assays to pharmaceutical standards for replicating and non-replicating M. abscessus. We have also tested a panel of 18 known anti-mycobacterial compounds. Assay development is currently underway to test compounds for activity against NTM in biofilm and inside macrophages as well. Conclusion To enhance hit identification for scaffolds to use as starting points for NTM drug development, focused libraries of compounds that have undergone significant preclinical profiling and/or compounds with known activity against M. tuberculosis (TB) will be screened. Such a “piggyback” approach usurps advances made in TB drug development and leverages them for NTM drug discovery. This will help expedite novel drug development, reduce attrition rate, and offer a shorter route to clinical use as it exploits the prior investment in medicinal chemistry, pharmacology, and toxicology. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Aya Shanti ◽  
Jeremy Teo ◽  
Cesare Stefanini
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Attrition Rate ◽  
Human Immune System ◽  
Drug Candidates ◽  
Immune Organs ◽  
On Chip ◽  
High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

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.

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