Detectives and helpers: Natural products as resources for chemical probes and compound libraries

Parthasarathy, Anutthaman; Mantravadi, Pavan K.; Kalesh, Karunakaran A.

doi:10.1016/j.pharmthera.2020.107688

Cited by 13 publications

(9 citation statements)

References 189 publications

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“…4B ) that closely mimics the chemical structure of tanespimycin but is equipped with a terminal alkyne tag for click chemistry and diazirine functionality ( 47 ) for photo-cross-linking of target proteins in proximity. The 17-mADAG probe was utilized in a live parasite competitive photoaffinity-based protein profiling (AfBPP) ( 33 – 35 ) coupled with iTRAQ quantitative proteomic MS ( Fig. 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…We also report a systematic chemical proteomics target validation of tanespimycin in L. mexicana . The combination of competitive activity/affinity-based protein profiling (ABPP/AfBPP) with quantitative proteomic MS has evolved as a powerful unbiased method for target and off-target profiling of biologically active agents ( 33 – 35 ). Our chemical proteomics target profiling using the novel tanespimycin analogue, the minimalist terminal alkyne diazirine compound 17-mADAG, revealed that the classical Hsp90 inhibitor not only engages with its presumed target Hsp90 in L. mexicana but also affects multiple proteins involved in protein synthesis and quality control.…”

Section: Discussionmentioning

confidence: 99%

“…The study defines the downstream effectors of Hsp90 inhibition in L. mexicana and provides precise relative quantitation of the effect of dose- and time-depended Hsp90 inhibition on hundreds of nascent parasite proteins. Additionally, we evaluated for the first time the target engagement of tanespimycin in L. mexicana using competitive affinity-based protein profiling (AfBPP) ( 33 – 35 ) with a novel minimalist terminal alkyne photoaffinity probe that closely mimics tanespimycin and revealed the protein target spectrum of the Hsp90 inhibitor in the parasite.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana

et al. 2021

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Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a large array of client proteins. The classical Hsp90 inhibitor tanespimycin has shown potent antileishmanial activity. Despite the increasing importance of Hsp90 inhibition in the development of antileishmanial agents, the global effects of these inhibitors on the parasite proteome remain unknown. By combining tanespimycin treatment with bioorthogonal noncanonical amino acid tagging (BONCAT) metabolic labeling and isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic mass spectrometry, for the first time, we robustly profiled the relative changes in the synthesis of hundreds of parasite proteins as functions of dose and duration of the inhibitor treatment. We showed that Hsp90 inhibition dynamically regulates nascent protein synthesis in Leishmania mexicana, with many chaperones and virulence factors showing inhibitor concentration- and treatment duration-dependent changes in relative expression. Many ribosomal proteins showed a downregulation upon severe Hsp90 inhibition, providing the first protein-level evidence that Hsp90 inhibition affects the protein synthesis capacity of the ribosome in this organism. We also provide an unbiased target validation of tanespimycin in L. mexicana using live parasite photoaffinity labeling with a novel chemical probe and quantitative proteomic mass spectrometry. We showed that the classical Hsp90 inhibitor not only engages with its presumed target, Hsp83-1, in L. mexicana promastigotes but also affects multiple proteins involved in protein synthesis and quality control in the parasite. This study defines the Leishmania parasites’ response to Hsp90 inhibition at the level of nascent global protein synthesis and provides a rich resource for future studies on Leishmania spp. biology and antileishmanial drug development. IMPORTANCE Leishmania spp. are the causative agents of leishmaniasis, a poverty-related disease, which is endemic in >90 countries worldwide, affecting approximately 12 million people, with an estimated 700,000 to 1 million new cases and around 70,000 deaths annually. Inhibitors of the chaperone protein Hsp90 have shown promising antileishmanial activity. However, further development of the Hsp90 inhibitors as antileishmanials is hampered by a lack of direct information of their downstream effects on the parasite proteome. Using a combination of mass spectrometry-based quantitative proteomics and chemical and metabolic labeling, we provide the first protein-level evidence that Hsp90 inhibition affects global protein synthesis in Leishmania. We also provide the precise relative quantitative changes in the expressions of hundreds of affected proteins as functions of both the concentration and duration of the inhibitor treatment. We find that Leishmania regulates its ribosomal proteins under Hsp90 inhibition while a set of virulence factors and chaperones are preferentially synthesized.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana

et al. 2021

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“…Researchers are attempting to develop new antifungal agents by optimizing agents within existing drug classes or by targeting novel mechanisms such as the calcineurin pathway, glycosylphosphatidylinositol (GPI) anchor biosynthesis, or farnesyltransferase inhibition. Other approaches include the use of molecules with other medicinal purposes (such as statins, which also interfere with cholesterol metabolism), the study of natural products with antifungal activity, biosynthesis, (2015) and the use of chemical probing methods or compound libraries (Amirkia and Heinrich, 2015;Robbins et al, 2016;Nami et al, 2019;Howard et al, 2020;Morio et al, 2020;Parthasarathy et al, 2020;Tavakkoli et al, 2020).…”

Section: Natural Products With Antifungal Activitymentioning

confidence: 99%

Natural Compounds With Antimicrobial and Antiviral Effect and Nanocarriers Used for Their Transportation

Stan

Enciu

Mateescu³

et al. 2021

Front. Pharmacol.

104

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Due to the increasing prevalence of life-threatening bacterial, fungal and viral infections and the ability of these human pathogens to develop resistance to current treatment strategies, there is a great need to find and develop new compunds to combat them. These molecules must have low toxicity, specific activity and high bioavailability. The most suitable compounds for this task are usually derived from natural sources (animal, plant or even microbial). In this review article, the latest and most promising natural compounds used to combat bacteria, filamentous fungi and viruses are presented and evaluated. These include plant extracts, essential oils, small antimicrobial peptides of animal origin, bacteriocins and various groups of plant compounds (triterpenoids; alkaloids; phenols; flavonoids) with antimicrobial and antiviral activity. Data are presented on the inhibitory activity of each natural antimicrobial substance and on the putative mechanism of action against bacterial and fungal strains. The results show that among the bioactive compounds studied, triterpenoids have significant inhibitory activity against coronaviruses, but flavonoids have also been shown to inhibit SARS-COV-2. The last chapter is devoted to nanocarriers used to improve stability, bioavailability, cellular uptake/internalization, pharmacokinetic profile and reduce toxicity of natural compunds. There are a number of nanocarriers such as liposomes, drug delivery microemulsion systems, nanocapsules, solid lipid nanoparticles, polymeric micelles, dendrimers, etc. However, some of the recent studies have focused on the incorporation of natural substances with antimicrobial/antiviral activity into polymeric nanoparticles, niosomes and silver nanoparticles (which have been shown to have intrinsic antimicrobial activity). The natural antimicrobials isolated from animals and microorganisms have been shown to have good inhibitory effect on a range of pathogens, however the plants remain the most prolific source. Even if the majority of the studies for the biological activity evaluation are in silico or in vitro, their internalization in the optimum nanocarriers represents the future of “green therapeutics” as shown by some of the recent work in the field.

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“… 18 Thus, studying the mechanisms of action of natural products is costly, time-consuming, and challenging. 19 The omics data hold promise for their use for identifying potential targets for the treatment of EC. 20 , 21 …”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Analysis and Experimental Pharmacology Study Explore the Mechanism of Gambogic Acid against Endometrial Cancer

Xia

Tang

2021

ACS Omega

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Endometrial cancer (EC) is one of the three most common gynecological cancers in female groups. Gambogic acid (GA), a natural caged xanthone, exerts significantly antitumor effects on many cancers. However, its efficacy on EC and pharmacological mechanism of action remain marginal up to now. This study suggested that GA had significant inhibitory effects on EC in vitro and in vivo, and no toxicity to normal cells or mice. In detail, GA suppressed cell proliferation, induced cell apoptosis, and cell cycle arrest at G 0 /G 1 stage, complied with the network pharmacology analysis, showed that the PI3K/Akt pathways were the most important signaling, and their protein and mRNA expression levels were confirmed by qRT-PCR and Western blot experiments. In all, our study first proved that GA could inhibit cell proliferation, induce cell apoptosis, and cell cycle arrest at G 0 /G 1 stage via the PI3K/Akt pathways, so GA would be a good therapy for EC.

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Detectives and helpers: Natural products as resources for chemical probes and compound libraries

Cited by 13 publications

References 189 publications

Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana

Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana

Natural Compounds With Antimicrobial and Antiviral Effect and Nanocarriers Used for Their Transportation

Network Pharmacology Analysis and Experimental Pharmacology Study Explore the Mechanism of Gambogic Acid against Endometrial Cancer

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