Mixed fermentation for natural product drug discovery

Natural products continue to play a major role in drug discovery and development. However, chemical redundancy is an ongoing problem. Genomic studies indicate that certain groups of bacteria and fungi have dozens of secondary metabolite pathways that are not expressed under standard laboratory growth conditions. One approach to more fully access the metabolic potential of cultivatable microbes is mixed fermentation, where the presence of neighboring microbes may induce secondary metabolite synthesis. Research to date indicates that mixed fermentation can result in increased antibiotic activity in crude extracts, increased yields of previously described metabolites, increased yields of previously undetected metabolites, analogues of known metabolites resulting from combined pathways and, importantly, induction of previously unexpressed pathways for bioactive constituents.     

Diversifying microbial natural products for drug discovery

Historically, nature has provided the source for the majority of the drugs in use today. More than 20,000 microbial secondary metabolites have been described, but only a small percentage of these have been carried forward as natural product drugs. Natural products are in tough competition with large chemical libraries and with combinatorial chemistries. Hence, each step of a natural product program has to be more efficient than ever, starting from the collection of environmental samples and the selection of strains, to metabolic expression, genetic exploitation, sample preparation and chemical dereplication. This review will focus on approaches for diversifying microbial natural product strains and extract libraries, while decreasing genetic and chemical redundancy.V. Knight and J.-J. Sanglier contributed equally to this work     

India takes an open source approach to drug discovery

Open source software may have been around for 17 years, but using an open source model to speed up drug discovery is a relatively new idea. This month, India is launching a new open source initiative for developing drugs to treat diseases such as tuberculosis, malaria, and HIV.     

Bioactive natural products from marine cyanobacteria for drug discovery

The prokaryotic marine cyanobacteria continue to be an important source of structurally bioactive secondary metabolites. A majority of these molecules are nitrogen-containing compounds biosynthesized by large multimodular nonribosomal polypeptide (NRP) or mixed polyketide-NRP enzymatic systems. A total of 128 marine cyanobacterial alkaloids, published in the literature between January 2001 and December 2006, are presented in this review with emphasis on their biosynthesis and biological activities. In addition, a number of highly cytotoxic compounds such as hectochlorin, lyngbyabellins, apratoxins, and aurilides have been identified as potential lead compounds for the development of anticancer agents. A brief coverage on the distribution of natural product biosynthetic genes as well as the mechanisms of tailoring enzymes involved in the biosynthesis of cyanobacterial compounds will also be given.     

Advanced tools in marine natural drug discovery

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New natural products as new leads for antibacterial drug discovery

Natural products have been a rich source of antibacterial drugs for many decades, but investments in this area have declined over the past two decades. The purpose of this review article is to provide a recent survey of new natural product classes and the mechanisms by which they work.     

Evaluation of target-specific natural compounds for drug discovery against Leishmaniasis

Leishmaniasis is a parasitic disease with no effective vaccine still now. Globally, it has affected millions of people, precisely in the undeveloped and developing countries. The control strategy for leishmaniasis depends only on chemotherapeutic methods that are associated with several side effects. Therefore, to overcome these negative impacts natural products are the best alternative for developing effective herbal-based drugs, which can act as one of the safest and effective alternative options to treat this particular disease. Leishmania, the causative agent of this disease possesses unique enzymes and metabolic pathways that are different from its mammalian host. Moreover, these unique enzymes, along with the signaling molecules and metabolic pathways that are crucial for its survival, serve as a suitable drug target for the evaluation of specific natural inhibitors to overcome leishmaniasis. Hence, in this review, we have discussed various specific targets of Leishmania, along with their natural inhibitors which can play a significant role in anti-leishmanial drug discovery.     

Venomics: a new paradigm for natural products-based drug discovery

The remarkable potency and pharmacological diversity of animal venoms has made them an increasingly valuable source of lead molecules for drug and insecticide discovery. Nevertheless, most of the chemical diversity encoded within these venoms remains uncharacterized, despite decades of research, in part because of the small quantities of venom available. However, recent advances in the miniaturization of bioassays and improvements in the sensitivity of mass spectrometry and NMR spectroscopy have allowed unprecedented access to the molecular diversity of animal venoms. Here, we discuss these technological developments in the context of establishing a high-throughput pipeline for venoms-based drug discovery.     

New aspects of natural products in drug discovery

During the past 15 years, most large pharmaceutical companies have decreased the screening of natural products for drug discovery in favor of synthetic compound libraries. Main reasons for this include the incompatibility of natural product libraries with high-throughput screening and the marginal improvement in core technologies for natural product screening in the late 1980s and early 1990 s. Recently, the development of new technologies has revolutionized the screening of natural products. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. Examples of these new advances and technologies are described in this review.     

Sulfur-containing marine natural products as leads for drug discovery and development

Among the large series of marine natural products (MNPs), sulfur-containing MNPs have emerged as potential therapeutic agents for the treatment of a range of diseases. Herein, we reviewed 95 new sulfur-containing MNPs isolated during the period between 2021 and March 2023. In addition, we discuss that the widely used strategies and the emerging technologies including natural product-based antibody drug conjugates (ADCs), small-molecule-based proteolysis targeting chimeras (PROTACs), nanotechnology-based drug carriers, artificial intelligence (AI)-driven drug discovery have been used for improving the efficiency and success rate of NP-based drug development. We also provide perspectives regarding the challenges and opportunities in sulfur-containing MNPs based drug discovery and development and future research directions.     

The impact of natural products upon modern drug discovery

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.     

Unlocking the potential of natural products in drug discovery

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.     

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

Abstract

Endophytes, microorganisms that colonize internal tissues of all plant species, create a huge biodiversity with yet unknown novel natural products, presumed to push forward the frontiers of drug discovery. Next to the clinically acknowledged antineoplastic agent, paclitaxel, endophyte research has yielded potential drug lead compounds with antibacterial, antiviral, antioxidant, insulin mimetic, anti-neurodegenerative and immunosuppressant properties. Furthermore, while being implicated in livestock neurotoxicosis, some endophyte-produced alkaloids have been shown to display insecticidal activity. The endophyte-host relationship is postulated to be a ‘balanced antagonism’. Moreover, the plausibility of horizontal gene transfer (HGT) hypothesis is taken into account. Knowledge of the genetic background of endophytic natural product biosynthesis is discussed on the basis of loline alkaloids, ergopeptines, lolitrems and maytansinoids. The current dynamic progress in genomics will contribute to a better understanding of endophytic microbes and to further exploiting them as a source of pharmaceutically relevant compounds.     

Triazole-linked reduced amide isosteres: an approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors

In the course of a β-site APP-cleaving enzyme 1 (BACE1) inhibitor discovery project an in situ synthesis/screening protocol was employed to prepare 120 triazole-linked reduced amide isostere inhibitors. Among these compounds, four showed modest (single digit micromolar) BACE1 inhibition. Our ligand design was based on a potent reduced amide isostere 1, wherein the P₂ amide moiety was replaced with an anti-1,2,3-triazole unit. Unfortunately, this replacement resulted in a 1000-fold decrease in potency. Docking studies of triazole-linked reduced amide isostere A3Z10 and potent oxadiazole-linked tertiary carbinamine 2a with BACE1 suggests that the docking poses of A3Z10 and 2a in the active sites are quite similar, with one exception. In the docked structures the placement of the protonated amine that engages D228 differs considerably between 2a and A3Z10. This difference could account for the lower BACE1 inhibition potency of A3Z10 and related compounds relative to 2a.