Natural products as drugs and tools for influencing core processes of eukaryotic mRNA translation

Burgers, Luisa D.; Fürst, Robert

doi:10.1016/j.phrs.2021.105535

Cited by 20 publications

(18 citation statements)

References 227 publications

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“…Females of the genus Paederus have been reported to use the toxin pederin to chemically defend themselves, their eggs and their offspring against predators [ 15 ]. Beyond that, this toxin was found to exhibit potent antitumor activity caused by selective inhibition of the eukaryotic ribosome [ 16 ]. In cytotoxicity assays using human carcinoma cell lines, IC 50 values in the subnanomolar range were observed [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Dermatitis linearis outbreak associated with Paederus balcanicus in Austria

Bakran-Lebl

Harmankaya²,

Fuehrer

et al. 2022

Wien Klin Wochenschr

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Summary Background Dermatitis linearis is a toxic skin lesion caused by contact with certain beetles of the genus Paederus (Coleoptera: Staphylinidae). Dermatitis linearis outbreaks have been described mainly in tropical and subtropical regions, but so far not in Central Europe, and are considered an emerging public health concern potentially associated with climate change. Material and methods Following diagnosis of dermatitis linearis in a cluster of six adults and one child with reported exposure to beetles with morphological characteristics of Paederus species at a recreational public open-air bath at Lake Neusiedl (Illmitz, Burgenland, Austria), we performed on-site inspection and installed light and pitfall traps. Collected beetle specimens of the genus Paederus were classified using morphological characteristics and DNA barcoding. Results A total of 32 Paederus beetles were collected using an aspirator (n = 2) and light traps (n = 30). No individuals of the genus Paederus were captured with the pitfall traps. Morphological analyses identified them as members of the Paederus balcanicus species, which was confirmed by genetic specification of four arbitrarily chosen individuals. Dermatitis linearis lesions were treated with topical steroids and healed but partly leaving scars and hyperpigmentation, over the course of a few weeks in all affected persons. Conclusion We report for the first time (a) an outbreak of dermatitis linearis associated with exposure to autochthonous Paederus species in Austria, and (b) that contact to the species Paederus balcanicus may cause dermatitis linearis in humans. Adequate measures should be taken to prevent dermatitis linearis outbreaks in areas with resident Paederus occurrence.

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Section: Discussionmentioning

confidence: 99%

Dermatitis linearis outbreak associated with Paederus balcanicus in Austria

Bakran-Lebl

Harmankaya²,

Fuehrer

et al. 2022

Wien Klin Wochenschr

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“…Sm interferes with peptide bond formation, a process that is essential to protein biosynthesis, on the large ribosomal subunit (50S and 60S) [ 8 ]. Sm binds primarily to the peptidyl (P) site and, because of the stabilization of the P-site/tRNA, the drug blocks the critical movement of tRNAs between the aminoacyl site and P-site, resulting in the inhibition of peptide bond formation and the inability of aminoacyl–tRNA to access the P-site [ 9 , 10 , 11 ]. Despite acute toxicity of Sm in mice [ 6 ] and Sm-related retinopathy in the phase I clinical study [ 12 ], an active testing program of the drug related to the protein biosynthesis machinery has continued [ 10 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Sparsomycin Exhibits Potent Antiplasmodial Activity In Vitro and In Vivo

et al. 2022

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The emerging spread of drug-resistant malaria parasites highlights the need for new antimalarial agents. This study evaluated the growth-inhibitory effects of sparsomycin (Sm), a peptidyl transferase inhibitor, against Plasmodium falciparum 3D7 (chloroquine-sensitive strain), P. falciparum K1 (resistant to multiple drugs, including chloroquine), P. yoelii 17XNL (cause of uncomplicated rodent malaria) and P. berghei ANKA (cause of complicated rodent malaria). Using a fluorescence-based assay, we found that Sm exhibited half-maximal inhibitory concentrations (IC50) of 12.07 and 25.43 nM against P. falciparum 3D7 and K1, respectively. In vitro treatment of P. falciparum 3D7 with Sm at 10 or 50 nM induced morphological alteration, blocked parasites in the ring state and prevented erythrocyte reinvasion, even after removal of the compound. In mice infected with P. yoelii 17XNL, the administration of 100 μg/kg Sm for 7 days did not affect parasitemia. Meanwhile, treatment with 300 μg/kg Sm resulted in a significantly lower parasitemia peak (18.85%) than that observed in the control group (40.13%). In mice infected with P. berghei ANKA, both four and seven doses of Sm (300 μg/kg) prolonged survival by 33.33%. Our results indicate that Sm has potential antiplasmodial activities in vitro and in vivo, warranting its further development as an alternative treatment for malaria.

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“…Intriguingly, but not totally surprisingly, the eukaryotic ribosome is also the target of naturally derived small molecule inhibitors (Figures 1 and 2, Supplementary Table S1 and Supplementary Session S1). Several compounds are known to hinder translation at different steps (Figure 1), as demonstrated by extensive functional works [24][25][26][27][28][29][30] (and reviewed in [31][32][33]). But until recently, no atomic-resolution information on the mode of action of ribosome inhibitors in eukaryotes was available.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective

Pellegrino

Terrosu

Yusupova

2021

Cancers

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Protein biosynthesis is a vital process for all kingdoms of life. The ribosome is the massive ribonucleoprotein machinery that reads the genetic code, in the form of messenger RNA (mRNA), to produce proteins. The mechanism of translation is tightly regulated to ensure that cell growth is well sustained. Because of the central role fulfilled by the ribosome, it is not surprising that halting its function can be detrimental and incompatible with life. In bacteria, the ribosome is a major target of inhibitors, as demonstrated by the high number of small molecules identified to bind to it. In eukaryotes, the design of ribosome inhibitors may be used as a therapy to treat cancer cells, which exhibit higher proliferation rates compared to healthy ones. Exciting experimental achievements gathered during the last few years confirmed that the ribosome indeed represents a relevant platform for the development of anticancer drugs. We provide herein an overview of the latest structural data that helped to unveil the molecular bases of inhibition of the eukaryotic ribosome triggered by small molecules.

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Natural products as drugs and tools for influencing core processes of eukaryotic mRNA translation

Cited by 20 publications

References 227 publications

Dermatitis linearis outbreak associated with Paederus balcanicus in Austria

Dermatitis linearis outbreak associated with Paederus balcanicus in Austria

Sparsomycin Exhibits Potent Antiplasmodial Activity In Vitro and In Vivo

Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective

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