Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein–protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein–protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.

Coupled translation-rotation eigenstates of in and on the spectroscopically optimized interaction potential: Effects of cage anisotropy on the energy level structure and assignments

We present an overview of solid-state NMR studies of endohedral H(2)-fullerene complexes, including (1)H and (13)C NMR spectra, (1)H and (13)C spin relaxation studies, and the results of (1)H dipole-dipole recoupling experiments. The available data involves three different endohedral H(2)-fullerene complexes, studied over a wide range of temperatures and applied magnetic fields. The symmetry of the cage influences strongly the motionally-averaged nuclear spin interactions of the endohedral H(2) species, as well as its spin relaxation behaviour. In addition, the non-bonding interactions between fullerene cages are influenced by the presence of endohedral hydrogen molecules. The review also presents several pieces of experimental data which are not yet understood, one example being the structured (1)H NMR lineshapes of endohedral H(2) molecules trapped in highly symmetric cages at cryogenic temperatures. This review demonstrates the richness of NMR phenomena displayed by H(2)-fullerene complexes, especially in the cryogenic regime.

5-Aminoimidazole-4-carboxamide ribonucleotide (known as ZMP) is a metabolite produced in de novo purine biosynthesis and histidine biosynthesis, but only utilized in the cell by a homodimeric bifunctional enzyme (called ATIC) that catalyzes the last two steps of de novo purine biosynthesis. ZMP is known to act as an allosteric activator of the cellular energy sensor adenosine monophosphate-activated protein kinase (AMPK), when exogenously administered as the corresponding cell-permeable ribonucleoside. Here, we demonstrate that endogenous ZMP, produced by the aforementioned metabolic pathways, is also capable of activating AMPK. Using an inhibitor of ATIC homodimerization to block the ninth step of de novo purine biosynthesis, we demonstrate that the subsequent increase in endogenous ZMP activates AMPK and its downstream signaling pathways. We go on to illustrate the viability of using this approach to AMPK activation as a therapeutic strategy with an in vivo mouse model for metabolic disorders.

No abstract