3-Amidinophenylalanine-Derived Matriptase Inhibitors can Modulate Hepcidin Production in vitro

Matriptase-2 (MT-2) is a type II transmembrane serine protease and predominantly attached to the surface of hepatocytes. MT-2 decreases the production of hepcidin, a key regulator of iron homeostasis. In this study, the effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 (MT-1/2) inhibitors (MI-432, MI-441, MI-460, and MI-461) on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 (IL-6 and IL-8) levels were determined and compared to controls. Hepcidin overproduction was observed in hepatocytes upon treatment with MI-432, MI-441 and MI-461 at 50 mu M. In contrast, extracellular hydrogen peroxide levels were not elevated significantly after matriptase inhibition with MI-461. Furthermore, MI-461 did not induce increases in IL-6 and IL-8 levels in these hepatic models. A model of the binding mode of inhibitor MI-461 in complex with MT-2 revealed numerous polar contacts contributing to the nanomolar potency of this compound. Based on the in vitro data on hepcidin regulation, treatment with MI-461 might be valuable in pathological states of iron metabolism without causing excessive oxidative stress

Synthesis and Crystal Structure of Benzyl [(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2-phenylethyl]carbamate

Peer reviewe

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

The authors thank Scott McMenemy for carrying out preliminary, early studies looking at effects of Gu compounds upon chicken embryology, as well as Charles D. Crowe, Jeffrey E. Roth, and Adam C. Rolt for critical comments on the article. fli1:EGFP zebrafish were obtained from the Zebrafish International Research Center (27). mpo:GFP zebrafish [also termed Tg(MPO:GFP)114] zebrafish were obtained from Dr. Stephen Renshaw, University of Sheffield (Sheffield, South Yorkshire, UK; ref. 29).Peer reviewedPostprin

Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes

The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies

Environmental sustainability in basic research:a perspective from HECAP+

The climate crisis and the degradation of the world's ecosystems require humanity to take immediate action. The international scientific community has a responsibility to limit the negative environmental impacts of basic research. The HECAP+ communities (High Energy Physics, Cosmology, Astroparticle Physics, and Hadron and Nuclear Physics) make use of common and similar experimental infrastructure, such as accelerators and observatories, and rely similarly on the processing of big data. Our communities therefore face similar challenges to improving the sustainability of our research. This document aims to reflect on the environmental impacts of our work practices and research infrastructure, to highlight best practice, to make recommendations for positive changes, and to identify the opportunities and challenges that such changes present for wider aspects of social responsibility

Environmental sustainability in basic research: a perspective from HECAP+

The climate crisis and the degradation of the world's ecosystems require humanity to take immediate action. The international scientific community has a responsibility to limit the negative environmental impacts of basic research. The HECAP+ communities (High Energy Physics, Cosmology, Astroparticle Physics, and Hadron and Nuclear Physics) make use of common and similar experimental infrastructure, such as accelerators and observatories, and rely similarly on the processing of big data. Our communities therefore face similar challenges to improving the sustainability of our research. This document aims to reflect on the environmental impacts of our work practices and research infrastructure, to highlight best practice, to make recommendations for positive changes, and to identify the opportunities and challenges that such changes present for wider aspects of social responsibility.Comment: 158 pages, 21 figures; comments welcome. Revisions included in Version 2.0 are detailed on page 3 of the pdf. If you would like to endorse this document please visit: https://sustainable-hecap-plus.github.io/. An HTML version of this document is available at: https://sustainable-hecap-plus.github.io

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–4

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action, or novel classes of drugs, which may inspire future medicinal chemistry endeavours devoted to addressing prime unmet medical needs

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs