A Guide to Targeting the Endocannabinoid System in Drug Design

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research

SARS-CoV-2 Papain-Like Protease Potential Inhibitors-In Silico Quantitative Assessment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs

Signaling through the primary cilium

© 2018 Wheway, Nazlamova and Hancock. The presence of single, non-motile "primary" cilia on the surface of epithelial cells has been well described since the 1960s. However, for decades these organelles were believed to be vestigial, with no remaining function, having lost their motility. It wasn't until 2003, with the discovery that proteins responsible for transport along the primary cilium are essential for hedgehog signaling in mice, that the fundamental importance of primary cilia in signal transduction was realized. Little more than a decade later, it is now clear that the vast majority of signaling pathways in vertebrates function through the primary cilium. This has led to the adoption of the term "the cells's antenna" as a description for the primary cilium. Primary cilia are particularly important during development, playing fundamental roles in embryonic patterning and organogenesis, with a suite of inherited developmental disorders known as the "ciliopathies" resulting from mutations in genes encoding cilia proteins. This review summarizes our current understanding of the role of these fascinating organelles in a wide range of signaling pathways

Utilizing the chicken as an animal model for human craniofacial ciliopathies

The chicken has been a particularly useful model for the study of craniofacial development and disease for over a century due to their relatively large size, accessibility, and amenability for classical bead implantation and transplant experiments. Several naturally occurring mutant lines with craniofacial anomalies also exist and have been heavily utilized by developmental biologist for several decades. Two of the most well known lines, talpid(2) (ta(2)) and talpid(3) (ta(3)), represent the first spontaneous mutants to have the causative genes identified. Despite having distinct genetic causes, both mutants have recently been identified as ciliopathic. Excitingly, both of these mutants have been classified as models for human craniofacial ciliopathies: Oral-facial-digital syndrome (ta(2)) and Joubert syndrome (ta(3)). Herein, we review and compare these two models of craniofacial disease and highlight what they have revealed about the molecular and cellular etiology of ciliopathies. Furthermore, we outline how applying classical avian experiments and new technological advances (transgenics and genome editing) with naturally occurring avian mutants can add a tremendous amount to what we currently know about craniofacial ciliopathies

Médicaments et aliments : approche ethnopharmacologique = Medicines and foods : ethnopharmacological approach

Au moins 500 espèces de plantes ont été utilisées comme remèdes traditionnels en Lituanie. Cette abondance de drogues végétales s'explique par les grandes ressources et la biodiversité de la flore lituanienne ainsi que par la richesse des traditions due à la diversité du peuplement. De nos jours, il est possible de trouver beaucoup de plantes médicinales vendues au marché de Vilnius (Wilno). Nombre d'entre elles ont des usages alimentaires et thérapeutiques. Nous avons mené des recherches sur le terrain (interviews de guérisseurs locaux, herboristes et autres, dans la région de Wilno) et entrepris des investigations botaniques et bibliographiques sur les plantes locales médicinales et alimentaires. Ces recherches ont permis de constater qu'un bon nombre de ces plantes suscitent actuellement un grand intérêt en raison des propriétés pharmacologiques qui leur ont été reconnues. Dans cet article sont présentés des exemples de plantes médicinales intéressantes et dignes d'attention, avec leurs usages et leurs indications. Parmi ces espèces, beaucoup semblent être des drogues de valeur, prometteuses dans le traitement de certains maux dits "de civilisation", ainsi que l'alcoolisme et les toxicomanies. Des remèdes végétaux tirés de la médecine traditionnelle pourraient aussi être utilisés dans les soins de santé primaire. (Résumé d'auteur

ECOTOXICITY AND PHYTOTOXICITY OF PLANT PROTECTION PRODUCTS TO RHIZOSPHERE FUNGI AND WINTER WHEAT SEEDLINGS

Registration of plant protection products involves the analysis of their effects on soil microorganisms. The residues of plant protection products penetrate the soil, but their impact on fungi remains scarcely researched. In this study, the influence of selected plant protection products on the abundance of rhizosphere-dwelling fungi and the growth of winter wheat seedlings was evaluated under greenhouse conditions. The analysed plant protection products had an inhibitory effect on the growth of filamentous fungi in the rhizosphere, whereas yeasts were resistant to those products applied to soil. Tebuconazole exerted the strongest suppressive effect on the growth of filamentous fungi, and propiconazole was characterized by the greatest phytotoxic activity against winter wheat seedlings. Azoxystrobin had the weakest ecotoxic and phytotoxic effects, and its application to soil usually led to a rapid increase in the counts of fungi of the genus Acremonium