scholarly journals Targeting tRNA-Synthetase Interactions towards Novel Therapeutic Discovery Against Eukaryotic Pathogens

2019 ◽  
Author(s):  
Paul Kelly ◽  
Fatemeh Hadi-Nezhad ◽  
Dennis Liu ◽  
Travis J. Lawrence ◽  
Roger G. Linington ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Broad Spectrum ◽  
Marine Natural Products ◽  
Drug Targets ◽  
Leishmania Major ◽  
Trna Synthetase ◽  
Cross Reactivity ◽  
Protein Synthesis Inhibitors ◽  
Macromolecular Interactions

AbstractThe development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and eight clades of trypanosomes, identifying parasite-specific informative features (including base-pairs and base mis-pairs) that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. These findings support a systems biology model in which combination chemotherapies that target multiple tRNA-synthetase interactions should be comparatively less prone to the emergence of resistance than conventional single drug therapies.Author SummaryTrypanosome parasites pose a significant health risk worldwide. Conventional drug development strategies have proven challenging given the high conservation between humans and pathogens, with off-target toxicity being a common problem. Protein synthesis inhibitors have historically been an attractive target for antimicrobial discovery against bacteria, and more recently for eukaryotic pathogens. Here we propose that exploiting pathogen-specific tRNA-synthetase interactions offers the potential for highly targeted drug discovery. To this end, we improved tRNA gene annotations in trypanosome genomes, identified functionally informative trypanosome-specific tRNA features, and showed that these features are highly conserved over approximately 250 million years of trypanosome evolution. Highlighting the species-specific and broad-spectrum potential of our approach, we identified natural product inhibitors against the parasite translational machinery that have no effect on the homologous human enzyme.

scholarly journals CMNPD: a comprehensive marine natural products database towards facilitating drug discovery from the ocean

2020 ◽  
Vol 49 (D1) ◽  
pp. D509-D515
Author(s):  
Chuanyu Lyu ◽  
Tong Chen ◽  
Bo Qiang ◽  
Ningfeng Liu ◽  
Heyu Wang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Terrestrial Plants ◽  
Activity Data ◽  
Related Data ◽  
Free Data ◽  
Pharmacokinetic Properties ◽  
Natural Products Discovery ◽  
User Friendly

Abstract Marine organisms are expected to be an important source of inspiration for drug discovery after terrestrial plants and microorganisms. Despite the remarkable progress in the field of marine natural products (MNPs) chemistry, there are only a few open access databases dedicated to MNPs research. To meet the growing demand for mining and sharing for MNPs-related data resources, we developed CMNPD, a comprehensive marine natural products database based on manually curated data. CMNPD currently contains more than 31 000 chemical entities with various physicochemical and pharmacokinetic properties, standardized biological activity data, systematic taxonomy and geographical distribution of source organisms, and detailed literature citations. It is an integrated platform for structure dereplication (assessment of novelty) of (marine) natural products, discovery of lead compounds, data mining of structure-activity relationships and investigation of chemical ecology. Access is available through a user-friendly web interface at https://www.cmnpd.org. We are committed to providing a free data sharing platform for not only professional MNPs researchers but also the broader scientific community to facilitate drug discovery from the ocean.

scholarly journals Marine natural products from sponges (Porifera) of the order Dictyoceratida (2013 to 2019); a promising source for drug discovery

RSC Advances ◽  
2020 ◽  
Vol 10 (57) ◽  
pp. 34959-34976
Author(s):  
Enas Reda Abdelaleem ◽  
Mamdouh Nabil Samy ◽  
Samar Yehia Desoukey ◽  
Miaomiao Liu ◽  
Ronald J. Quinn ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Biological Activities ◽  
Marine Organisms ◽  
Promising Source ◽  
Secondary Natural Products

Marine organisms have been considered an interesting target for the discovery of different classes of secondary natural products with wide-ranging biological activities.

scholarly journals Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

scholarly journals Natural product drug discovery in the artificial intelligence era

2022 ◽  
Author(s):  
Fernanda I Saldivar-Gonzalez ◽  
Victor Daniel Aldas-Bulos ◽  
José Luis Medina-Franco ◽  
Fabien Plisson
Keyword(s):  
Artificial Intelligence ◽  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Protein Drug ◽  
Privileged Structures

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even...

Marine natural products drug discovery from actinomycetes at fundacion MEDINA

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
JR Tormo ◽  
D Oves ◽  
R Lacret ◽  
C Moreno ◽  
M DeLa Cruz ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products

scholarly journals Drug Discovery on Natural Products: From Ion Channels to nAChRs, from Nature to Libraries, from Analytics to Assays

2019 ◽  
Vol 24 (3) ◽  
pp. 362-385 ◽  
Author(s):  
Reka A. Otvos ◽  
Kristina B. M. Still ◽  
Govert W. Somsen ◽  
August B. Smit ◽  
Jeroen Kool
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Ion Channels ◽  
Ion Channel ◽  
Bioactive Compounds ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Drug Targets ◽  
Α7 Nachr ◽  
Analytical Approaches

Natural extracts are complex mixtures that may be rich in useful bioactive compounds and therefore are attractive sources for new leads in drug discovery. This review describes drug discovery from natural products and in explaining this process puts the focus on ion-channel drug discovery. In particular, the identification of bioactives from natural products targeting nicotinic acetylcholine receptors (nAChRs) and serotonin type 3 receptors (5-HT3Rs) is discussed. The review is divided into three parts: “Targets,” “Sources,” and “Approaches.” The “Targets” part will discuss the importance of ion-channel drug targets in general, and the α7-nAChR and 5-HT3Rs in particular. The “Sources” part will discuss the relevance for drug discovery of finding bioactive compounds from various natural sources such as venoms and plant extracts. The “Approaches” part will give an overview of classical and new analytical approaches that are used for the identification of new bioactive compounds with the focus on targeting ion channels. In addition, a selected overview is given of traditional venom-based drug discovery approaches and of diverse hyphenated analytical systems used for screening complex bioactive mixtures including venoms.

Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

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.

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