Featured
-
-
Article |
Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3
The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.
- Hao-Yuan Wang
- , Haojun Yang
- & Jack Taunton
-
Article |
Filling of a water-free void explains the allosteric regulation of the β1-adrenergic receptor by cholesterol
The β1-adrenergic receptor (β1AR) contains empty cavities in its preactive conformation, which disappear in the active one. Now, using X-ray crystallography of xenon-derivatized β1AR crystals, a cavity has been shown to be in contact with the cholesterol-binding pocket. Monitoring the binding of a cholesterol analogue in solution has explained the function of cholesterol as a negative allosteric modulator of β1AR.
- Layara Akemi Abiko
- , Raphael Dias Teixeira
- & Stephan Grzesiek
-
Article |
Evolution of dynamical networks enhances catalysis in a designer enzyme
Computationally designed enzymes can be substantially improved by directed evolution. Now, it has been shown that evolution can introduce a dynamic network that selectively tightens the transition-state ensemble, giving rise to a negative activation heat capacity. Targeting such transition state conformational dynamics may expedite de novo enzyme creation.
- H. Adrian Bunzel
- , J. L. Ross Anderson
- & Adrian J. Mulholland
-
-
Article |
Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms
Screening commercial kinase inhibitors for antibacterial activity identified the anticancer drug sorafenib as a major hit. Subsequent structure–activity optimization created a new antibacterial analogue with high potency against methicillin-resistant Staphylococcus aureus, including challenging persisters and biofilms, as well as demonstrating efficacy in an in vivo mouse model. The mode of action involves stimulation of protein secretion and inhibition of menaquinone biosynthesis.
- Philipp Le
- , Elena Kunold
- & Stephan A. Sieber
-
Article |
Targeted photoredox catalysis in cancer cells
Current photodynamic therapy photosensitizers require oxygen; however, tumours are often hypoxic. Now, an organoiridium complex with an unusually high redox potential, which is effective in normoxia and hypoxia, has been developed. The organoiridium complex kills cancer cells by an immunogenic apoptotic mechanism involving efficient photocatalytic oxidation of NADH to NAD radicals, and reduction of cytochrome c.
- Huaiyi Huang
- , Samya Banerjee
- & Peter J. Sadler
-
Article |
Salinomycin kills cancer stem cells by sequestering iron in lysosomes
Cancer stem cells are typically refractory to conventional treatments. Now, an unprecedented mechanism has been discovered by which salinomycin and derivatives can sequester iron in lysosomes leading to cytoplasmic iron depletion and the subsequent production of reactive oxygen species that are lethal to the cell. This discovery of the importance of iron in cancer stem cell maintenance provides an opportunity for developing new therapeutics.
- Trang Thi Mai
- , Ahmed Hamaï
- & Raphaël Rodriguez
-
-
Article |
Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor
Molecular inhibitors of amyloid formation could help combat Alzheimer's disease, type 2 diabetes, and other major human diseases. Here, two-dimensional infrared spectroscopy and residue-specific isotope labelling are used to obtain detailed structural information on amyloid-inhibitor complexes. The unexpected behaviour observed helps to explain the moderate activity of the inhibitor studied.
- Chris T. Middleton
- , Peter Marek
- & Martin T. Zanni
-
Article |
Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host–cell interaction
Oligosaccharides displayed at cell surfaces have important biological functions — such as controlling the entry of viruses — but a full understanding of this behaviour requires the synthesis of such compounds, which remains challenging. Here, two synthetic octasaccharides were shown to have remarkably similar inhibition of herpes simplex virus type 1 infection of cell cultures to the natural oligosaccharide identified in enzymatic studies.
- Yu-Peng Hu
- , Shu-Yi Lin
- & Shang-Cheng Hung