Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors

Replacement of the piperidine ring in the lead benzenesulfonamide Na_v1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Na_v1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Na_v1.7 inhibitors. This report describes the synthesis and SAR of these analogs.     

Exploiting a water network to achieve enthalpy-driven,bromodomain-selective BET inhibitors

Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC₅₀ values comparable to BET inhibitor (BETi) clinical candidates.     

9-Aminoacridine-based agents impair the bovine viral diarrhea virus (BVDV) replication targeting the RNA-dependent RNA polymerase (RdRp)

Bovine viral diarrhea virus (BVDV) infection is still a plague that causes important livestock pandemics. Despite the availability of vaccines against BVDV, and the implementation of massive eradication or control programs, this virus still constitutes a serious agronomic burden. Therefore, the alternative approach to combat Pestivirus infections, based on the development of antiviral agents that specifically inhibit the replication of these viruses, is of preeminent actuality and importance.Capitalizing from a long-standing experience in antiviral drug design and development, in this work we present and characterize a series of small molecules based on the 9-aminoacridine scaffold that exhibit potent anti-BVDV activity coupled with low cytotoxicity. The relevant viral protein target – the RNA-dependent RNA polymerase – the binding mode, and the mechanism of action of these new antivirals have been determined by a combination of in vitro (i.e., enzymatic inhibition, isothermal titration calorimetry and site-directed mutagenesis assays) and computational experiments. The overall results obtained confirm that these acridine-based derivatives are promising compounds in the treatment of BVDV infections and, based on the reported structure-activity relationship, can be selected as a starting point for the design of a new generation of improved, safe and selective anti-BVDV agents.     

Effect of intraoperative local application of 3% hydrogen peroxide on pocket infections following cardiac implantable electronic device implantation: An observational study

Aims

The aim of this study was to analyze whether local application of 3% hydrogen peroxide (H2O2) additionally to standard antibiotic prophylaxis following implantation of cardiac implantable electronic devices (CIED) reduces the incidence of pocket infections (PI).

Dopamine Modulates Option Generation for Behavior

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A variable undecad repeat domain in cavin1 regulates caveola formation and stability

Caveolae are plasma membrane invaginations involved in transport, signalling and mechanical membrane sensing in metazoans. Their formation depends upon multiple interactions between membrane‐embedded caveolins, lipids and cytosolic cavin proteins. Of the four cavin family members, only cavin1 is strictly required for caveola formation. Here, we demonstrate that an eleven residue (undecad) repeat sequence (UC1) exclusive to cavin1 is essential for caveolar localization and promotes membrane remodelling through binding to phosphatidylserine. In the notochord of mechanically stimulated zebrafish embryos, the UC1 domain is required for caveolar stability and resistance to membrane stress. The number of undecad repeats in the cavin1 UC1 domain varies throughout evolution, and we find that an increased number also correlates with increased caveolar stability. Lastly, we show that the cavin1 UC1 domain induces dramatic remodelling of the plasma membrane when grafted into cavin2 suggesting an important role in membrane sculpting. Overall, our work defines a novel conserved cavin1 modular domain that controls caveolar assembly and stability.     

Studies of modern Italian dog populations reveal multiple patterns for domestic breed evolution

Through thousands of years of breeding and strong human selection, the dog (Canis lupus familiaris) exists today within hundreds of closed populations throughout the world, each with defined phenotypes. A singular geographic region with broad diversity in dog breeds presents an interesting opportunity to observe potential mechanisms of breed formation. Italy claims 14 internationally recognized dog breeds, with numerous additional local varieties. To determine the relationship among Italian dog populations, we integrated genetic data from 263 dogs representing 23 closed dog populations from Italy, seven Apennine gray wolves, and an established dataset of 161 globally recognized dog breeds, applying multiple genetic methods to characterize the modes by which breeds are formed within a single geographic region. Our consideration of each of five genetic analyses reveals a series of development events that mirror historical modes of breed formation, but with variations unique to the codevelopment of early dog and human populations. Using 142,840 genome‐wide SNPs and a dataset of 1,609 canines, representing 182 breeds and 16 wild canids, we identified breed development routes for the Italian breeds that included divergence from common populations for a specific purpose, admixture of regional stock with that from other regions, and isolated selection of local stock with specific attributes.     

Consequences of the timing of seed release of Erythronium americanum (Liliaceae), a deciduous forest myrmecochore

Myrmecochores are plants with seeds adapted for ant dispersal. This specialized dispersal syndrome may provide Erythronium americanum seeds with protection from predators within the eastern deciduous forests. To determine the adaptive significance of myrmecochory in E. americanum, seed removal rates and seed predation in relation to seed release date and location along the Potomac River in Langley, Virginia, were examined. The number of seeds removed from four exclosure treatments were monitored two times in 1992 and three times in 1993 within floodplain and hilltop populations of E. americanum. Overall, seed removal was greatest from control depots, and E. americanum seeds were removed at nearly the same rate from predator-exclusion depots, indicating that removal from open depots is largely due to ant removal. Ants removed significantly more seeds than predators in the first 48 h of seed exposure and could potentially remove all E. americanum seeds before nightfall. Aphaenogaster rudis was identified as the primary disperser of E. americanum. Seeds placed in depots after the natural seed release period were discovered more quickly and removed by ants at a significantly higher rate than seeds released at the natural date. These results suggest that ant dispersal of E. americanum seeds reduces the likelihood of seed predation.