Research progress of drug toxicity mechanism based on the gut microbiota / 药学学报

The exploration of drug toxicity and mechanisms is a vital component in ensuring the safe use of drugs in clinical practice, as this topic has attracted widespread concern. The intestinal flora holds great significance for drug metabolism, efficacy and mechanism, and is an instrumental metabolic organ that facilitates material information transfer and biotransformation. However, an increasing number of studies have shown that intestinal bacteria are closely related to the toxicity of specific drugs. On the one hand, drugs are transformed into toxic metabolites under the influence of intestinal bacteria, thus inducing direct drug toxicity. On the other hand, the composition and function of the intestinal flora are altered under drug influence, resulting in disruption of endogenous metabolic pathways. Consequently, this disruption compromises the intestinal barrier and affects other organs, leading to indirect drug toxicity. This review meticulously compiles recent examples of drug toxicity attributed to intestinal bacteria, explores in depth the contention that metabolic enzymes of gut microbiota may be of great influence on oral drug toxicity, and outlines prospective avenues for future research on gut microbiota and drug toxicity and mechanisms. This not only provides novel perspectives for the judicious clinical utilization of drugs but also offers insights for the safety assessment of innovative pharmaceuticals.

The research of liver-targeted drugs based on asialoglycoprotein receptor / 药学学报

Asialoglycoprotein receptor (ASGPR) is highly expressed on the surface of parenchymal liver cells. It can specifically recognize and bind to desialylated glycoproteins which contain terminal galactose or N-acetylgalactosamine residues, and endocytosed by clathrin-mediated endocytosis, transported and then degraded in lysosome. Based on this character, ASGPR mediated liver-targeted drug delivery is likely to increase drug distribution, reduce potential side effects and lower dose. This article reviewed the expression, structure, ligand binding and endocytosis of ASGPR, and summarized the design and optimization of ASGPR ligands and the release strategies. Finally, we put forward some expects about the clinical drug development for ASGPR.

The function and drug development progress of free fatty acid receptor 1 in chronic inflammatory diseases / 药学学报

As a member of G protein coupled-receptors superfamily, free fatty acid receptor 1 (FFAR1), is also known as GPR40, has been shown to regulate numerous pathophysiological processes in a variety of tissues and organs. The activated FFAR1 has a variety of biological functions. For instance, it can not only regulate metabolism of fatty acids and glucose, but also play an important role in immune inflammatory response, it may be a potential drug target for the treatment of various chronic inflammatory diseases. In this review, we focus on the recent researches of FFAR1's action in the regulation of pathophysiological processes, its molecular mechanism and new agonists development. At the same time, this review will take the discovery of series FFAR1 agonists as examples, and display the applied prospects of FFAR1.

Meanings of polysaccharides in traditional Chinese medicines decoction from the viewpoint of its gut microbiota regulation effects / 药学学报

Decoction is one of the traditional dosage forms of traditional Chinese medicines (TCMs). In addition to small molecular components, decoction also contains polysaccharides and other macromolecular components. For a long time, ethanol precipitation has been commonly used during TCMs based new drug development to remove "ineffective macromolecular components", and enrich "active small molecules components", so as to improve the subsequent formability of the preparations. With the recognition of the relationships between gut microbiota and host health/disease, and the potential prebiotic effects of natural polysaccharides, the important values of polysaccharides in TCMs decoctions have been gradually emerged. Based on the representative findings of our own research and the literatures, the potential prebiotics function of TCMs polysaccharides were reviewed regarding its related effects on host physiological and pathological processes of metabolic function, bowel function, immunity, inflammation, emotion and tumor, on the metabolism and absorption of coexisting small molecule components, as well as the structure-function features, so that the meanings of polysaccharides in TCMs decoction were discussed and emphasized, and hopefully to provide enlightenment for the premise of attaching importance to the existence of polysaccharide components in the process of innovative drug research and development based on classical and clinical TCMs prescriptions.

Progress on research and development of drug for chronic kidney disease and related comorbidities / 药学学报

Chronic kidney disease (CKD) is a progressive disease with many complications (eg, cardiovascular disease and acidosis and anemia) and high morbidity and mortality occurs in the population. There is no cure for this disease, current treatments including renin-angiotensin-aldosterone pathway inhibitors and sodium-glucose co-transporter 2 inhibitors can only delay the progression to end-stage renal disease. With the identification of more key factors and mechanisms in CKD development, new potential therapeutic approaches for CKD can be developed. This review summarizes the mainstays of therapy and strategies for CKD and related comorbidities to support the development of novel treatments.

The mechanism of androgen independent signaling pathway in castration-resistant prostate cancer and the research progress on related drugs / 药学学报

Prostate cancer is one of the common malignant tumors of male urogenital system, and the incidence of prostate cancer in China has increased significantly in the past decade. At present, endocrine therapy based on androgen blockade is the main method of clinical treatment except radical surgery and radiotherapy/chemotherapy for prostate cancer. However, the clinical benefit can only be obtained in the early stage of treatment, and nearly 90% of patients will develop to the castration resistance, and among them, nearly 90% of patients will have bone metastasis. The quality of life decreases sharply with the progression of disease for patients. In addition to the androgen signal pathway, studies have shown that many other oncogenic signal pathways have involved in the development of castration resistance, including classic cancer signaling pathways, immune and inflammatory signaling pathways, etc. Understanding the mechanism of androgen independent signal pathway in the formation of castration resistance will help to understand the off-target effect of androgen blocking therapy and introduce new treatment targets or strategies to get rid of the "no drug available" dilemma for clinical treatment of castration resistance.

Recent progress in targeting degradation of FAK based on PROTAC / 药学学报

Local focal adhesion kinase (FAK) is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation, development, metastasis and invasion, and is considered to be an important target for the development of antineoplastic drugs. It has both kinase-dependent and non-kinase-dependent scaffolding functions. However, traditional small molecular inhibitors can only inhibit its kinase-dependent activity, so it is difficult to target the kinase-independent scaffolding function. Therefore, there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors. Proteolysis targeting chimera (PROTAC) is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system. The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein, thus eliminating the scaffolding function of FAK. In this review, FAK protein, the signaling pathway, and small molecule inhibitors are briefly described, and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.

Advances in snake venom studies: from lethal toxins to new drug development / 药学学报

Snake bite is a common acute and severe disease in tropical and subtropical regions, and its public health importance has been largely neglected. Snake venom is a complex mixture of active proteins, polypeptides, and other toxins. Many of these components can target multiple ion channels, cell receptors, and membrane transporters. Compared with traditional small molecule drugs, the proteins and polypeptides from snake venom have stronger specificity and affinity to targets and are especially suitable for novel drug design. The current studies show that snake venom and its components have great potential for development as leading compounds of new drugs. In this paper, the recent advances in main components, toxic effects, and detoxification strategies of snake venom, as well as its pharmacological activities and medical application are reviewed. The aim is to provide reference for clinical diagnosis and treatment of snake bite and development of new drugs based on snake venom.

Protein targets of medicinally active molecules based on their original structures and molecular probes / 药学学报

Medicinally active molecules are those that have pharmacological effects. Research on protein targets of these molecules not only clarifies their mechanism of action, but also deepens our understanding of biological systems. Here we review recent advances in protein targets of drugs used in clinical practice or in preclinical research. They have various functions including anti-inflammatory, anti-malarial, anti-tumor and other biological activities. Activity-based protein profiling (ABPP) and cellular thermal shift assay (CETSA) are two useful methods to identify the protein targets of small molecules. ABPP depends on a derivative active molecule probe to pull down the protein targets to reveal the interaction mechanisms between the active molecules and targets. Drug target engagement also can be assessed by means of CETSA based on ligand-induced changes in protein thermal stability. In the CETSA approach, the active molecules do not need to be chemically modified. Combining the CETSA method with quantitative mass spectrometry is an effective approach to study the effect of compounds on the thermal profile of a cellular proteome and identify the protein targets. ABPP and CETSA can be complementary and effectively clarify the protein targets. The study of protein targets will help reveal the mechanism of action of medicinal molecules, reveal toxic mechanisms and aid in the discovery of new medicinal targets to promote the process of drug development.

Progress in research and development of cognition related drugs / 药学学报

Nervous system drugs play an important role in the drug research and development, and the cognition related drug become the urgent needs of social development. However, drugs which can regulate cognitive function are seriously inadequate in clinical supply, and faced frustration in research and development process. In this paper, a brief overview of the two types of cognition related drugs (drugs affecting normal cognitive function and improving cognitive dysfunction) were discussed based on the current research status of cognitive pharmacology. The current research and development of new cognition related drugs focuses on regulating neurotransmitters, targeting Aβ and Tau proteins, neuroprotection and vascularization, and still requires new research methods and ideas. In this article, we summed up the research strategies based on the clinical and development of cognition related drugs, especially for the Alzheimer's disease, then we put forward the task and challenge of cognitive pharmacology development. We aimed at providing new ideas for researchers to promote the development of cognitive drugs.

First-in-class small molecule drugs in 2018 / 药学学报

In 2018, FDA approved 59 kinds of new drugs in all, breaking the record of 53 set in 1993. There were 34 types of small molecule drugs, which accounted for 64% of the whole new drugs. Of these 34 new small molecule drugs, 9 first-in-class ones marked a milestone for the subsequent drug discovery and development. These include Glasdegib, the world's first small molecule inhibitor targeting Smo through Hedgehog signaling pathway; Ivosidenib, the first small molecule inhibitor targeting mutant IDH1; Tecovirimat, the first small molecule drug for anti-variola virus therapy through targeting p37; Baloxavir marboxil, the first anti-flu drug targeting cap-dependent endonuclease; Elagolix sodium, the first small molecule inhibitor in treating endometriosis by targeting GnRH-R, etc. The research and development of first-in-class drugs is always full of obstacles and challenges. However, once they were successfully recognized as the "heavy bomb" drugs, they would become huge benefits. This article chose the representative first-in-class small molecule drugs that were approved in 2018 as examples to analyze their development processes in an attempt to provide guidance for the research and development of more first-in-class drugs.