nanomolar concentration
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2021 ◽  
Author(s):  
Exequiel Porta ◽  
Shane Wilkinson ◽  
María Sol Ballari ◽  
Babu Tekwani ◽  
Guillermo Labadie

A series of thirty 1,2,3-triazolylsterols were prepared by a stereocontrolled synthesis and inspired by azasterols with proven antiparasitic activity. Ten of these compounds constitute chimeras/hybrids of AZA and 1,2,3-triazolyl azasterols. The entire library was assayed against the etiological agents of the parasites responsible of kinetoplastid diseases (L. donovani, T. cruzi and T. brucei). Several of the compounds were active at submicromolar/nanomolar concentration with excellent selectivity index, when compared to their activity in mammalian cells. Studies of the physicochemical properties in silico were conducted to rationalize the activities.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Min Bai ◽  
Hui Huang ◽  
Jian Hao ◽  
Ji Zhang ◽  
Haibo Wu ◽  
...  

Editor's Note: this Article has been retracted; the Retraction Note is available at 10.1038/s41598-021-91478-8.


2021 ◽  
Author(s):  
Valeria Napolitano ◽  
Agnieszka Dabrowska ◽  
Kenji Schorpp ◽  
Andre Mourao ◽  
Emilia Barreto-Duran ◽  
...  

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.


Author(s):  
Dmitry G. Tovbin ◽  
Dmitry N. Tarasov ◽  
Dmitry V. Malakhov ◽  
Natalia A. Tserkovnikova ◽  
Arseniy V. Aybush ◽  
...  

Background: Despite the introduction of direct oral anticoagulants, the search for new oral anticoagulants remains an urgent task. Objective: Using the docking and scoring, based on physical methods, simple chemical rules, methods of synthesis and activity measurement, to develop new low-molecular-weight inhibitors of factor Xa, which are potential anticoagulants. Method: The development of leads was based on chemical synthesis and the structure-based drug design methods. The basic idea is to combine the two approaches: one based on predictive modeling, and the other – on the experimental data. Results: In frame of our concept we developed some nanomolar leads. Further chemical modification improved the inhibition constant by more than one order. Discussion: The method proposed in this paper, as well as other methods, includes virtual screening, screening, chemical synthesis and activity measurement. However, the most time – consuming process in this method (chemical synthesis) was decided to simplify and reduce the cost to the extent that it could be allowed: a very simple chemical reaction was chosen - the formation of an amide bond. Conclusion: In this work, we demonstrated how, using simple chemical rules, based on the structure-based drug design, substances with a nanomolar concentration of activity can be developed. Using our method, we developed substances with nanomolar concentration of activity. Further chemical modification of this leads improved the inhibition constant by more than one order.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Trinda Anne Ting ◽  
Alexandre Chaumet ◽  
Frederic Andre Bard

Abstract Biologics such as peptides and antibodies are a well-established class of therapeutics. However, their intracellular delivery remains problematic. In particular, methods to efficiently inhibit intra-nuclear targets are lacking. We previously described that Pseudomonas Exotoxin A reaches the nucleoplasm via the endosomes-to-nucleus trafficking pathway. Here, we show that a non-toxic truncated form of PE can be coupled to peptides and efficiently reach the nucleoplasm. It can be used as a Peptide Nuclear Delivery Device (PNDD) to deliver polypeptidic cargos as large as Glutathione- S-transferase (GST) to the nucleus. PNDD1 is a fusion of PNDD to the c-myc inhibitor peptide H1. PNDD1 is able to inhibit c-Myc dependent transcription at nanomolar concentration. In contrast, H1 fused to various cell-penetrating peptides are active only in the micromolar range. PNDD1 attenuates cell proliferation and induces cell death in various tumor cell lines. In particular, several patient-derived Diffuse Large B-Cell Lymphomas cell lines die after exposure to PNDD1, while normal B-cells survive. Altogether, our data indicate that PNDD is a powerful tool to bring active cargo to the nucleus and PNDD1 could be the basis of a new therapy against lymphoma.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Junhyung Cho ◽  
Young Jae Lee ◽  
Je Hyoung Kim ◽  
Sang il Kim ◽  
Sung Soon Kim ◽  
...  

Abstract The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as hypertension and cardiac diseases have a higher mortality rate. An efficient strategy in response to this issue is repurposing drugs with antiviral activity for therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases that have antiviral activity against several coronaviruses. Thus, we aimed to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentrations (IC50) of DIG and OUA were determined at a nanomolar concentration. Progeny virus titers of single-dose treatment of DIG, OUA and remdesivir were approximately 103-, 104- and 103-fold lower (> 99% inhibition), respectively, than that of non-treated control or chloroquine at 48 h post-infection (hpi). Furthermore, therapeutic treatment with DIG and OUA inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. Collectively, these results suggest that DIG and OUA may be an alternative treatment for COVID-19, with potential additional therapeutic effects for patients with cardiovascular disease.


2020 ◽  
Vol 77 (3) ◽  
pp. 1339-1351
Author(s):  
Michela Guglielmotto ◽  
Giusi Manassero ◽  
Valeria Vasciaveo ◽  
Marika Venezia ◽  
Massimo Tabaton ◽  
...  

Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.


2020 ◽  
Author(s):  
Trinda Anne Ting ◽  
Alexandre Chaumet ◽  
Frederic Bard

AbstractBiologics such as peptides and antibodies are a well-established class of therapeutics. However, their intracellular delivery remains problematic. In particular, methods to efficiently inhibit intra-nuclear targets are lacking. We previously described that Pseudomonas Exotoxin A reaches the nucleoplasm via the endosomes-to-nucleus trafficking pathway. Here, we show that a non-toxic truncated form of PE can be coupled to peptides and efficiently reach the nucleoplasm. It can be used as a Peptide Nuclear Delivery Device (PNDD) to deliver polypeptidic cargos as large as Glutathione-S-transferase (GST) to the nucleus. PNDD1 is a fusion of PNDD to the c-myc inhibitor peptide H1. PNDD1 is able to inhibit c-Myc dependent transcription at nanomolar concentration. In contrast, H1 fused to various cell-penetrating peptides are active only in the micromolar range. PNDD1 attenuates cell proliferation and induces cell death in various tumor cell lines. In particular, several patient-derived Diffuse Large B-Cell Lymphomas cell lines die after exposure to PNDD1, while normal B-cells survive. Altogether, our data indicate that PNDD is a powerful tool to bring active cargo to the nucleus and PNDD1 could be the basis of a new therapy against lymphoma.


2019 ◽  
Vol 66 (2) ◽  
pp. 11-17
Author(s):  
E. Kurin ◽  
P. Mučaji ◽  
M. Nagy

Abstract Resveratrol and caffeic acid belong to plant polyphenols and are known for their antioxidant effects. The aim of our research was to study their impact on Maillard reaction. This one occurs when the reducing saccharides react with amino groups of biomolecules including proteins, alter their protein conformation and transform to the variety of advanced glycation end products (AGEs). AGEs exhibit browning and generate fluorescence. There exist expectations that this oxidative protein glycosylation could be prevented by antioxidants. In this study, we incubated bovine serum albumin (BSA) with glucose for 7 days at 37°C and measured characteristic fluorescence and UV absorbance of the formed AGEs. Surprisingly, resveratrol and caffeic acid enhanced transformation of BSA to glycation products, which was confirmed either when cupric Cu(II) or ferric Fe(III) ions in nanomolar concentration were added to the system as pro-oxidant agent.


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