Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new ...molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life.
In vivo
,
in vitro
, and
in silico
tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability.
Glycogen synthase kinase‐3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen synthase (GS) in response to insulin ...stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms of GSK3, GSK3α, and GSK3β, have been implicated in many biological and pathophysiological processes. The various functions of GSK3 are indicated by its widespread distribution in multiple cell types and tissues. The studies of GSK3 activity using animal models and the observed effects of GSK3‐specific inhibitors provide more insights into the roles of GSK3 in regulating energy metabolism and homeostasis. The cross‐talk between GSK3 and some important energy regulators and sensors and the regulation of GSK3 in mitochondrial activity and component function further highlight the molecular mechanisms in which GSK3 is involved to regulate the metabolic activity, beyond its classical regulatory effect on GS. In this review, we summarize the specific roles of GSK3 in energy metabolism regulation in tissues that are tightly associated with energy metabolism and the functions of GSK3 in the development of metabolic disorders. We also address the impacts of GSK3 on the regulation of mitochondrial function, activity and associated metabolic regulation. The application of GSK3 inhibitors in clinical tests will be highlighted too. Interactions between GSK3 and important energy regulators and GSK3‐mediated responses to different stresses that are related to metabolism are described to provide a brief overview of previously less‐appreciated biological functions of GSK3 in energy metabolism and associated diseases through its regulation of GS and other functions.
The connection between lipoprotein (a) Lp(a) levels and the risks of cardiovascular disease and diabetes remains poorly understood. Lp(a) is encoded by the LPA gene, and evidence suggests that the ...kringle IV type 2 (KIV-2) variant is particularly important to Lp(a) isoform size. A large isoform size, represented as a high number of KIV-2 repeats in LPA, is associated with low serum Lp(a) concentrations and an increased risk of type 2 diabetes. We investigated the associations among Lp(a) concentrations, LPA KIV-2 repeats, and type 2 diabetes in a Chinese population of 1,863 consecutive patients with very high cardiovascular risk, as identified by coronary angiography. Individuals with Lp(a) levels in the top tertile 67.86 (35.34–318.50) mg/dl had a lower risk of diabetes compared with those in the bottom tertile 7.38 (0.60–12.91) mg/dl. There was an inverse association between the number of KIV-2 repeats and serum Lp(a) concentrations. This study demonstrated that a high number of LPA KIV-2 repeats are associated with increased risk of type 2 diabetes in a Chinese population with very high cardiovascular risk, which suggests that large Lp(a) isoform size, associated with low Lp(a) concentration, has a causal effect on type 2 diabetes.
Reaction phenotyping provides critical information regarding the fraction metabolized (f
) of drug candidates. It has become increasingly important in drug discovery and development as it can be used ...to assess victim drug-drug interaction potential, guide structural modification to reduce f
, inform clinical study design, predict individual variability in pharmacokinetics, and evaluate the impact of genetic polymorphisms. Areas covered: The currently available in vitro and in vivo methods for reaction phenotyping are summarized along with their advantages, limitations and timings for application during the different stages of drug discovery and development. Challenges of reaction phenotyping for low clearance compounds, non-Cytochrome P450 (CYP) enzymes, extrahepatic contribution and atypical kinetics are highlighted and various approaches are discussed. Expert opinion: Certain areas of reaction phenotyping remain challenging with the current state of the science. In order to better define f
in this challenging space, there needs to be future advances in selective inhibitors and specific substrate reactions for non-CYP enzymes, availability of high quality and low cost recombinant enzymes, tissue distribution and in vitro-in vivo correlation, scaling factors for extrahepatic enzymes and the next generation of low clearance tools.
Zheng Guanying paid close attention to the issue of the spread of Christianity in China since his youth. Over a period of more than three decades, he produced five monographs specifically addressing ...Christianity, from unequivocally opposing the spread of Christianity in China in the mid-to-late 1870s, to advocating for the adoption of the preaching form of the Christian “gatherings every seven days” to disseminate the village covenants and sacred edicts among the Chinese people in the 1890s. He proposed that the Chinese people should hold the right to spread Christianity. In 1906, he advocated for the establishment of a “common religion” and proposed “one religion for all nations” to eliminate wars around the world. In his later years, he proposed the “Five great wishes” to integrate and govern the various religions of the world with Taoism as the core, attempting to reconstruct global order from the perspective of religious unity. He envisioned the establishment of a sacred Taoist monastery, the dissemination of religious concepts, and the cultivation of talents, which drew on the organizational structure and missionary methods of Christianity, reflecting the thinking and efforts of modern Chinese intellectuals to bridge the Chinese and Western civilizations, seek solutions for modern China, reconcile conflicts between China and the West, and pursue global unity.
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