Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of , with an IC of 64.

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light.

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor () of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene.

Medicinal chemistry of metal chelating fragments in metalloenzyme active sites: A perspective.

Numerous metal-containing enzymes (metalloenzymes) have been considered as drug targets related to diseases such as cancers, diabetes, anemia, AIDS, malaria, bacterial infection, fibrosis, and neurodegenerative diseases. Inhibitors of the metalloenzymes have been developed independently, most of which are mimics of substrates of the corresponding enzymes. However, little attention has been paid to the interactions between inhibitors and active site metal ions.

Click Chemistry-Based Discovery of [3-Hydroxy-5-(1 H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia.

As a gene associated with anemia, the erythropoiesis gene is physiologically expressed under hypoxia regulated by †hypoxia-inducing factor-α (HIF-α). Thus, stabilizing HIF-α is a potent strategy to stimulate the expression and secretion of erythropoiesis. In this study, we applied click chemistry to the discovery of HIF prolyl hydroxylase 2 (HIF-PHD2) inhibitors for the first time, and a series of triazole compounds showed preferable inhibitory activity in fluorescence polarization assays.

Application of in-vitro screening methods on hypoxia inducible factor prolyl hydroxylase inhibitors.

Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-α (HIF-α), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-α, which may lead to the degradation of HIF-α and eventually cause disenabling the expression of erythropoietin.

Complete Genome Sequence of GQJK2, a Plant Growth-Promoting Rhizobacterium with Antifungal Activity.

GQJK2 is a plant growth-promoting rhizobacterium with antifungal activity which was isolated from L. rhizosphere. Here, we report the complete genome sequence of GQJK2.

Overexpression of the rubisco activase gene improves growth and low temperature and weak light tolerance in Cucumis sativus.

Rubisco activase (RCA) is an important enzyme that can catalyze the carboxylation and oxygenation activities of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), which is involved in the photosynthetic carbon reduction cycle. Here, we studied the effects of changes in RCA activity on photosynthesis, growth and development, as well as the low temperature and weak light tolerance of RCA overexpressing transgenic cucumber (Cucumis sativus) plants. CsRCA overexpression increased the plant height, leaf area and dry matter, and decreased the root/top ratio in transgenic cucumber plants compared with the wild-type (WT) plants.

Coalition Formation and Spectrum Sharing of Cooperative Spectrum Sensing Participants.

In cognitive radio networks, self-interested secondary users (SUs) desire to maximize their own throughput. They compete with each other for transmit time once the absence of primary users (PUs) is detected. To satisfy the requirement of PU protection, on the other hand, they have to form some coalitions and cooperate to conduct spectrum sensing.

[Impacts of suboptimal temperature and low light intensity on the activities and gene expression of photosynthetic enzymes in cucumber seedling leaves].

Taking the cucumber cultivar 'Jinyou 3' as test material, this paper studied the variations of the mRNA expression and activities of ribulose-1, 5-bisphosphate carboxylase/oxygenase (Rubisco), fructose-1, 6-bisphosphatase (FBPase), glyceraldehydes-3-phosphate dehydrogenase (GAPDH), fructose-1, 6-bisphosphate aldolase (FBA), and transketolase (TK) in cucumber seedling leaves under suboptimal temperature and low light intensity (ST+LL). In the treatment of ST+LL, the leaf area and the dry mass per plant decreased remarkably, compared with the control. On the early days of ST+LL treatment, the gene expression of Rubisco rbcL and rbcS, FBPase, GAPDH, FBA, and TK declined markedly, the activities of the enzymes except TK obviously weakened, and the photosynthetic rate (P(n)) decreased rapidly.

[Responses of Rubisco and Rubisco activase in cucumber seedlings to low temperature and weak light].

Using 'Jinyou 3' cucumber seedlings as test materials, this paper studied their photosynthetic rate (P(n)), Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and Rubisco activase (RCA) activities, and gene expression of Rubisco and RCA under optimal temperature and weak light (WL: 25 degrees C/18 degrees C, 100 micromol x m(-2) x s(-1)), suboptimal temperature and weak light (ST+WL: 18 degrees C/12 degrees C, 100 micromol x m(-2) x s(-1)), and low temperature and weak light (LT+WL: 10 degress C/5 degrees C, 100 micromol x m(-2) x s(-1)). Comparing with the control (25 degrees C/18 degrees C, 400 micromol x m(-2) x s(-1)), treatments WL, ST+WL, and LT+WL all led to a remarkable decrease in leaf area and dry matter mass. At initial stage, the P(n), Rubisco activity, rbcL and rbcS expression, RCA activity, and CsRCA expression in the three treatments declined by a big margin; 5-7 days later, these parameters tended to be less changed in treatment WL, ascended slowly in treatment ST+WL, and decreased continuously in treatment LT+WL.