Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.
The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistance bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-D-Thr-OH), has a single purification step and a good recovery (22). By using this approach we have synthesised two teixobactin analogues and established that the D-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules
Human angiogenin (ANG), the first member of the angiogenin family (from the pancreatic ribonuclease A superfamily) to be identified, is an angiogenic factor that induces neovascularization. It has received much attention due to its involvement in the growth of tumors and its elevated expression level in pancreatic and several other cancers. Recently the biological role of ANG has been shown to extend to the nervous system. Mutations in ANG have been linked with familial as well as sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by selective destruction of motor neurons. Furthermore, mouse angiogenin-1 has been shown to be expressed in the developing nervous system and during the neuronal differentiation of pluripotent stem cells. We have now characterized the seven variants of ANG reported in ALS patients with respect to the known biochemical properties of ANG and further studied the biological properties of three of these variants. Our results show that the ribonucleolytic activity of six of the seven ANG-ALS implicated variants is significantly reduced or lost and some variants also show altered thermal stability. We report a significant reduction in the cell proliferative and angiogenic activities of the three variants that we chose to investigate further. Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.Amyotrophic lateral sclerosis (ALS) 1 is a fatal neurodegenerative disorder characterized by selective destruction of motor neurons (1). In the past decade, a small number of genes involved in the etiology of the disease have been identified (for a recent review see ref 2). The best studied of these is SOD1 (3), the gene for Cu/Zn superoxide dismutase. More than a hundred SOD1 mutations have now been linked with ALS, and motor neuron death from many of these mutations has been shown to result from a toxic gain of function rather than loss of dismutase activity. However, mutations in SOD1 account for only 1-2% of all cases of ALS and 20% of the familial cases. Some of the other proteins implicated in ALS are the vesicle-trafficking protein VAPB (4); ALSIN, a putative guanine nucleotide factor for GTPase (5); and senataxin (6). In addition, vascular endothelial growth factor (VEGF), an angiogenic factor that plays an important role in motor neuron survival, has been linked with ALS (7-10). However, the causes and molecular mechanisms underlying ALS are still largely unclear, and effective therapies do not appear to be imminent. Angiogenin (ANG), which encodes an angiogenic protein, was recently identified as a candidate susceptibility gene for ALS in the Irish and Scottish population by Greenway et al. (11). In a further study of over 2500 individuals from five independent populations from northern Europe and North America, Greenway et al. (12) found seven missense mutations (Figure 1) in 11 unrelated individuals with sporadic ALS and in f...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.