6 research outputs found
Mass spectrometric screening of transcriptional regulators involved in antibiotic biosynthesis in Streptomyces coelicolor A3(2)
Identification of Multiple 5‑HT<sub>4</sub> Partial Agonist Clinical Candidates for the Treatment of Alzheimer’s Disease
The cognitive impairments observed in Alzheimer’s
disease (AD) are in part a consequence of reduced acetylcholine (ACh)
levels resulting from a loss of cholinergic neurons. Preclinically,
serotonin 4 receptor (5-HT<sub>4</sub>) agonists are reported to modulate
cholinergic function and therefore may provide a new mechanistic approach
for treating cognitive deficits associated with AD. Herein we communicate
the design and synthesis of potent, selective, and brain penetrant
5-HT<sub>4</sub> agonists. The overall goal of the medicinal chemistry
strategy was identification of structurally diverse clinical candidates
with varying intrinsic activities. The exposure–response relationships
between binding affinity, intrinsic activity, receptor occupancy,
drug exposure, and pharmacodynamic activity in relevant preclinical
models of AD were utilized as key selection criteria for advancing
compounds. On the basis of their excellent balance of pharmacokinetic
attributes and safety, two lead 5-HT<sub>4</sub> partial agonist candidates <b>2d</b> and <b>3</b> were chosen for clinical development
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia
Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules
Pharmacological Potential of Phylogenetically Diverse Actinobacteria Isolated from Deep-Sea Coral Ecosystems of the Submarine Avilés Canyon in the Cantabrian Sea
The Family Streptomycetaceae
The family Streptomycetaceae comprises the genera Streptomyces, Kitasatospora, and Streptacidiphilus that are very difficult to differentiate both with genotypic and phenotypic characteristics. A separate generic status for Kitasatospora and Streptacidiphilus is questionable. Members of the family can be characterized as non-acid-alcohol-fast actinomycetes that generate most often an extensively branched substrate mycelium that rarely fragments. At maturity, the aerial mycelium forms chains of few to many spores. A large variety of pigments is produced, responsible for the color of the substrate and aerial mycelium. The organisms are chemoorganotrophic with an oxidative type of metabolism and grow within different pH ranges. Streptomyces are notable for their complex developmental cycle and production of bioactive secondary metabolites, producing more than a third of commercially available antibiotics. Antibacterial, antifungal, antiparasitic, and immunosuppressant compounds have been identified as products of Streptomyces secondary metabolism. Streptomyces can be distinguished from other filamentous actinomycetes on the basis of morphological characteristics, in particular by vegetative mycelium, aerial mycelium, and arthrospores. The genus comprises at the time of writing more than 600 species with validated names. 16S rRNA gene sequence-based analysis for species delineation within the Streptomycetaceae is of limited value. The variations within the 16S rRNA genes—even in the variable regions—are too small to resolve problems of species differentiation and to establish a taxonomic structure within the genus. Comprehensive comparative studies including protein-coding gene sequences with higher phylogenetic resolution and genome-based studies are needed to clarify the species delineation within the Streptomycetaceae