scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

2021 ◽  
Vol 14 (3) ◽  
pp. 203 ◽  
Author(s):  
Shurong Hou ◽  
Juan Diez ◽  
Chao Wang ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
De Novo ◽  
Selective Inhibitors ◽  
Preclinical Development ◽  
Starting Point ◽  
Good Starting Point ◽  
Parallel Screening ◽  
Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

2020 ◽  
Author(s):  
Shurong Hou ◽  
Juan Diez ◽  
Chao Wang ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
High Throughput ◽  
Inhibitory Activity ◽  
De Novo ◽  
Clinical Development ◽  
Selective Inhibitors ◽  
Parallel Screening ◽  
Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in pre-clinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultra-high throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified 5 selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These are the most selective inhibitors of meprin α to date.

scholarly journals Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4206 ◽  
Author(s):  
Qi Li ◽  
Hongyu Yang ◽  
Jun Mo ◽  
Yao Chen ◽  
Yue Wu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Inhibitory Activity ◽  
Skin Pigmentation ◽  
Competitive Inhibitor ◽  
Tyrosinase Inhibitor ◽  
Starting Point ◽  
Good Starting Point ◽  
Tyrosinase Inhibitors ◽  
Dopa Formation ◽  
Potent Inhibitory Activity

Targeting tyrosinase is considered to be an effective way to control the production of melanin. Tyrosinase inhibitor is anticipated to provide new therapy to prevent skin pigmentation, melanoma and neurodegenerative diseases. Herein, we report our results in identifying new tyrosinase inhibitors. The shape-based virtual screening was performed to discover new tyrosinase inhibitors. Thirteen potential hits derived from virtual screening were tested by biological determinations. Compound 5186-0429 exhibited the most potent inhibitory activity. It dose-dependently inhibited the activity of tyrosinase, with the IC50 values 6.2 ± 2.0 µM and 10.3 ± 5.4 µM on tyrosine and L-Dopa formation, respectively. The kinetic study of 5186-0429 demonstrated that this compound acted as a competitive inhibitor. We believe the discoveries here could serve as a good starting point for further design of potent tyrosinase inhibitor.

scholarly journals Advances on the Implementation of Circular Economy Techniques in Rural Areas in Colombia under a Sustainable Development Framework

2021 ◽  
Vol 13 (7) ◽  
pp. 3816
Author(s):  
Javier Rodrigo-Ilarri ◽  
Camilo-A. Vargas-Terranova ◽  
María-Elena Rodrigo-Clavero ◽  
Paula-A. Bustos-Castro
Keyword(s):  
Sustainable Development ◽  
Waste Management ◽  
Circular Economy ◽  
Rural Areas ◽  
Development Framework ◽  
Starting Point ◽  
Management Plans ◽  
Good Starting Point ◽  
Depressed Regions ◽  
First Time

For the first time in the scientific literature, this research shows an analysis of the implementation of circular economy techniques under sustainable development framework in six municipalities with a depressed economy in Colombia. The analysis is based on solid waste data production at a local scale, the valuation of the waste for subsequent recycling, and the identification and quantification of the variables associated with the treatment and final disposal of waste, in accordance with the Colombian regulatory framework. Waste generation data are obtained considering three different scenarios, in which a comparison between the simulated values and those established in the management plans are compared. Important differences have been identified between the waste management programs of each municipality, specifically regarding the components of waste collection, transportation and disposal, participation of environmental reclaimers, and potential use of materials. These differences are fundamentally associated with the different administrative processes considered for each individual municipality. This research is a good starting point for the development of waste management models based on circular economy techniques, through the subsequent implementation of an office tool in depressed regions such as those studied.

scholarly journals Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

2021 ◽  
Vol 22 (13) ◽  
pp. 7236
Author(s):  
Endah Dwi Hartuti ◽  
Takaya Sakura ◽  
Mohammed S. O. Tagod ◽  
Eri Yoshida ◽  
Xinying Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Chemical Library ◽  
New Class ◽  
De Novo Biosynthesis ◽  
Starting Point ◽  
Novel Drugs ◽  
Low Toxicity ◽  
Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

scholarly journals Computational Analysis of African Swine Fever Virus Protein Space for the Design of an Epitope-Based Vaccine Ensemble

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1078 ◽  
Author(s):  
Albert Ros-Lucas ◽  
Florencia Correa-Fiz ◽  
Laia Bosch-Camós ◽  
Fernando Rodriguez ◽  
Julio Alonso-Padilla
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
De Novo ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Fever Virus ◽  
Economic Losses ◽  
Virus Protein ◽  
Hemorrhagic Disease ◽  
Starting Point

African swine fever virus is the etiological agent of African swine fever, a transmissible severe hemorrhagic disease that affects pigs, causing massive economic losses. There is neither a treatment nor a vaccine available, and the only method to control its spread is by extensive culling of pigs. So far, classical vaccine development approaches have not yielded sufficiently good results in terms of concomitant safety and efficacy. Nowadays, thanks to advances in genomic and proteomic techniques, a reverse vaccinology strategy can be explored to design alternative vaccine formulations. In this study, ASFV protein sequences were analyzed using an in-house pipeline based on publicly available immunoinformatic tools to identify epitopes of interest for a prospective vaccine ensemble. These included experimentally validated sequences from the Immune Epitope Database, as well as de novo predicted sequences. Experimentally validated and predicted epitopes were prioritized following a series of criteria that included evolutionary conservation, presence in the virulent and currently circulating variant Georgia 2007/1, and lack of identity to either the pig proteome or putative proteins from pig gut microbiota. Following this strategy, 29 B-cell, 14 CD4+ T-cell and 6 CD8+ T-cell epitopes were selected, which represent a starting point to investigating the protective capacity of ASFV epitope-based vaccines.

Industry-Sponsored Medical Education — In the Quest for Professional Integrity and Legal Certainty

2007 ◽  
Vol 14 (4) ◽  
pp. 313-319
Author(s):  
Benedikt Buchner
Keyword(s):  
Medical Education ◽  
Self Regulation ◽  
State Regulation ◽  
General Question ◽  
Legal Certainty ◽  
European Directive ◽  
Starting Point ◽  
Good Starting Point ◽  
Advertising Law ◽  
The Right

AbstractIndustry-sponsored medical education is a much disputed issue. So far, there has been no regulatory framework which provides clear and definite rules as to whether and under what circumstances the sponsorship of medical education is acceptable. State regulation does not exist, or confines itself to a very general principle. Professional regulation, even though applied frequently, is rather vague and indefinite, raising the general question as to whether self-regulation is the right approach at all. Certainly, self-regulation by industry cannot and should not replace other regulatory approaches. Ultimately, advertising law in general and the European Directive 2001/83/EC specifically, might be a good starting point in providing legal certainty and ensuring the independence of medical education. Swiss advertising law illustrates how the principles of the European Directive could be implemented clearly and unambiguously.

scholarly journals Multiple Myeloma Inhibitory Activity of Plant Natural Products

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2678
Author(s):  
Karin Jöhrer ◽  
Serhat Sezai Ҫiҫek
Keyword(s):  
Multiple Myeloma ◽  
Natural Products ◽  
Myeloma Cell ◽  
Myeloma Cell Line ◽  
Antiproliferative Effects ◽  
Plant Natural Products ◽  
Starting Point ◽  
Human Myeloma Cell Line ◽  
Group A ◽  
Good Starting Point

A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure–activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced and selective induction of apoptosis when substituted in position 7 of the isoquinoline moiety. Interestingly, out of the phenolic compound class, two of the most noteworthy constituents belong to the relatively small subclass of xanthones, rendering this group a good starting point for possible further drug development. The class of terpenoids also provides noteworthy constituents, such as the highly oxygenated diterpenoid oridonin, which exhibited antiproliferative effects equal to those of bortezomib on RPMI8226 cells. Moreover, triterpenoids containing a lactone ring and/or quinone-like substructures, e.g., bruceantin, whitaferin A, withanolide F, celastrol, and pristimerin, displayed remarkable activity, with the latter two compounds acting as inhibitors of both NF-κB and proteasome chymotrypsin-like activity.

COVID-19, Business, and Human Rights

2021 ◽  
Vol 23 (5) ◽  
pp. 433-449
Author(s):  
Surya Deva
Keyword(s):  
Human Rights ◽  
Full Range ◽  
International Human Rights Law ◽  
Human Rights Law ◽  
International Human Rights ◽  
Economic Problems ◽  
Business And Human Rights ◽  
Starting Point ◽  
Good Starting Point ◽  
International Human

Abstract COVID-19 has affected the full range of human rights, though some rights holders have experienced a disproportionate impact. This has triggered debate about the respective obligations and responsibilities of states and business enterprises under international human rights law. Against this backdrop, this article examines critically whether the “protect, respect and remedy” framework operationalised by the UN Guiding Principles on Business and Human Rights is “fit for the purpose” to deal with the COVID-19 crisis. I argue that while the UNGPs’ framework provides a good starting point, it is inadequate to bring transformative changes to overcome deep-rooted socio-economic problems exposed by this pandemic. Realising human rights fully would not only require harnessing the potential of states’ tripartite obligations, but also move beyond limiting the responsibility of businesses to respect human rights.

Water Depollution Control : A Gateway to Reaction Monitoring and Analytical Chemistry

2021 ◽  
Author(s):  
Martin Tiano ◽  
Max Roose
Keyword(s):  
Analytical Chemistry ◽  
Undergraduate Students ◽  
Environmental Chemistry ◽  
Organic Pollutant ◽  
Internal Standard ◽  
Experimental Session ◽  
Reaction Monitoring ◽  
Starting Point ◽  
Good Starting Point ◽  
Magnetite Particles

<div>We present here an experimental session for undergraduate students, based on the reaction monitoring of the degradation of an organic pollutant (para-nitrophenol) by a Fenton-like reaction, catalysed by magnetite particles. <br></div><div>During the session, students realized a follow-up of the reaction by Gas Chromatography with an internal standard, and by UV-Visible spectrophotometry. <br></div>This session was a good starting point to numerous discussions about analytical chemistry, environmental chemistry.

What Neuroscience Can Tell about Intuitive Processes in the Context of Perceptual Discovery

2006 ◽  
Vol 18 (12) ◽  
pp. 2077-2087 ◽  
Author(s):  
Kirsten G. Volz ◽  
D. Yves von Cramon
Keyword(s):  
Initial Guess ◽  
Future Research ◽  
Starting Point ◽  
Sensory Modalities ◽  
Direct Contrast ◽  
Good Starting Point ◽  
Lateral Portion ◽  
Definition Of ◽  
Conscious Attention ◽  
Potential Content

According to the Oxford English Dictionary, intuition is “the ability to understand or know something immediately, without conscious reasoning.” Most people would agree that intuitive responses appear as ideas or feelings that subsequently guide our thoughts and behaviors. It is proposed that people continuously, without conscious attention, recognize patterns in the stream of sensations that impinge upon them. What exactly is being recognized is not clear yet, but we assume that people detect potential content based on only a few aspects of the input (i.e., the gist). The result is a vague perception of coherence which is not explicitly describable but instead embodied in a “gut feeling” or an initial guess, which subsequently biases thought and inquiry. To approach the nature of intuitive processes, we used functional magnetic resonance imaging when participants were working at a modified version of the Waterloo Gestalt Closure Task. Starting from our conceptualization that intuition involves an informed judgment in the context of discovery, we expected activation within the median orbito-frontal cortex (OFC), as this area receives input from all sensory modalities and has been shown to be crucially involved in emotionally driven decisions. Results from a direct contrast between intuitive and nonintuitive judgments, as well as from a parametric analysis, revealed the median OFC, the lateral portion of the amygdala, anterior insula, and ventral occipito-temporal regions to be activated. Based on these findings, we suggest our definition of intuition to be promising and a good starting point for future research on intuitive processes.

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