Development Of Innovative Drugs Research Articles

Molecular Mechanisms of Hawthorn Extracts in Multiple Organs Disorders in Underlying of Diabetes: A Review.

Diabetes mellitus (DM) is one of the most important metabolic disorders associated with chronic hyperglycemia and occurs when the body cannot manage insulin secretion, insulin action, or both. Autoimmune destruction of pancreatic beta cells and insulin resistance are the major pathophysiological factors of types 1 and 2 of DM, respectively. Prolonged hyperglycemia leads to multiple organs dysfunctions, including nephropathy, neuropathy, cardiomyopathy, gastropathy, and micro- and macrovascular disorders. The basis of the metabolic abnormalities in carbohydrate, fat, and protein in diabetes is insufficient action of insulin on various target tissues. Medicinal plants are rich sources of bioactive chemical compounds with therapeutic effects. The beneficial effects of leaves, fruits, and flowers extracts of Crataegus oxyacantha, commonly called hawthorn, belonging to the Rosaceae family, are widely used as hawthorn-derived medicines. Data in this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2021. Based on this review, hawthorn extracts appear both therapeutic and protective effects against diabetic-related complications in various organs through molecular mechanisms, such as decreasing triglyceride, cholesterol, very low density lipoprotein and increasing the antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, total antioxidant capacity, decreasing malondialdehyde level, and attenuating tumor necrosis factor alpha, interleukin 6 and sirtuin 1/AMP-activated protein kinase (AMPK)/nuclear factor kappa B (NF-κB) pathway and increasing the phosphorylation of glucose transporter 4, insulin receptor substrate 1, AKT and phosphoinositide 3-kinases, and attenuating blood sugar and regulation of insulin secretion, insulin resistance, and improvement of histopathological changes in pancreatic beta cells. Collectively, hawthorn can be considered as one new target for the research and development of innovative drugs for the prevention or treatment of DM and related problems.

Study on Sustainable China’s Pharmaceutical Innovation Ecosystem

In recent years, China's pharmaceutical innovation has achieved remarkable results, with strong growth in innovative drug development driven by policy, talent, and investment. Through more than 20 years of development, China has initially established a relatively complete drug regulatory system of laws and regulations. At the same time, China's pharmaceutical innovation is also facing many challenges, including policy, talent, and investment. However, compared to the world's leading countries, there is still a gap in the quality of innovation in China's currently marketed pharmaceutical innovation ecosystem. By implementing the concept of scientific and risk-based assessment, this paper provides a comprehensive analysis of the current state of China's pharmaceutical innovation ecosystem and proposes future directions for development, including improving laws, regulations, policies, and technical guidelines promptly; improving the review decision-making mechanism and priority review mechanism to encourage the review of innovative drugs; optimising the organisational structure, approval process and resource allocation of regulatory bodies in a demand-driven manner to shorten the review time; and strengthening the clinical data.

Commentary: Indirect action pattern: A remote and cross-organ pharmacological mechanism for drug innovation

The research and development (R&D) of innovative drugs is limited by the low success rates and high attrition of drug candidates, representing an unmet demand for healthy life. A methodological breakthrough of new drug R&D may breed acceleration. In the current issue, Clemens et al. reported a novel indirect action pattern of phosphatidic acid (PA) in an acetaminophen (APAP)-induced liver toxicity model. In this model, PA acted on a remote tissue – epididymal white adipose tissue (eWAT) firstly, and then induced eWAT-derived interlukin-6 as intermediate substance (IMS) to protect against APAP-induced liver injury, while had no effect on the primary disease site–liver. Of note, several recent studies also suggested that besides the conventional methodology of directly targeting the disease primary organ/site, utilizing endogenous substances (e.g., cytokines, microRNA, functional metabolites, or hormones) as IMS to achieve therapeutic purpose should also be considered during new drugs R&D, which we call it indirect action (INDA) here. Taking together, a fundamental breakthrough may be achieved when exploring the new drug R&D methodology from the perspective of INDA, indicating a potential strategy for drug innovation.

Development and Validation of the HPLC Method for Quantification of the Innovative Drug DD217, Factor Xa Inhibitor, in Rat Plasma for a Pharmacokinetic Study

Introductio n . Nowadays, discovery and development of innovative drugs represent a relevant goal for the pharmaceutical market. One of such drugs is N-(5-chloropyridine-2-yl)-2-({4-[ethanimidoyl(methyl)benzoyl}amino)-5-methylbenzamide hydrochloride (hereinafter DD217), an innovative drug that belongs to the class of anticoagulants, namely factor Xa inhibitors. Aim. The aim of this study was to develop and validate a method for DD217 determination in rat plasma by means of high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) to carry out pharmacokinetic studies. Materials and methods. Outbred Wistar rats were used in the study. Rats received a single dose of DD217 substance solution intragastrically at a dose of 5, 15, 30 mg/kg. The validated HPLC-MS/MS method was employed for DD217 determination in rat plasma. Nebivolol was chosen as the internal standard of the method. Chromatographic separation involved the use of Phenomenex Luna С8 column (3 µm, 50 × 4.6 mm) and gradient elution with water-acetonitrile solution containing 0.1 % formic acid. The total run time of each sample was equal to 2.0 min. DD217 and nebivolol were detected in positive electrospray ionization mode, the ion transitions monitored were m/z 436,1 → 119,9 and 406,0 → 151,0, respectively. Pharmacokinetic parameters and descriptive statistics were calculated through model-independent method in IBM SPSS Statistics v27 and Julia v1.6.0 (MixedModels v3.8.0, ClinicalTrialUtilities v0.5.1) software. Results and discussion. Method was validated by linearity, lower limit of quantification, selectivity, accuracy and precision, dilution integrity, matrix effect, recovery, carry-over, and stability. The lower limit of quantification of DD217 in rat plasma was 2.0 ng/mL. The method was successfully applied for establishing the pharmacokinetic parameters of DD217 substance in rat plasma after intragastric administration at a dose of 5, 15, 30 mg/kg. Conclusion. HPLC-MS/MS method for DD217 determination in plasma was developed, validated and applied in order to evaluate pharmacokinetic parameters of DD217 substance in rat plasma.

Quantitative system pharmacology as a legitimate approach to examine extrapolation strategies used to support pediatric drug development.

Extrapolation strategies from adult data for designing pediatric drug development programs are explored using the quantitative systems pharmacology (QSP) modeling approach, a mechanistic drug and disease modeling framework that can predict clinical response and guide pediatric drug development in general. This innovative model‐informed drug discovery and development approach can leverage adult‐pediatric pharmacology and disease similarity metrics to validate extrapolation assumptions. We describe the QSP model strategy and framework for extrapolation to design pediatric drug development programs by leveraging adult data across a wide range of therapeutic areas and illustrating stage‐gate decisions informed by such an approach.

The Potential Role of Gut Microbial-Derived Exosomes in Metabolic-Associated Fatty Liver Disease: Implications for Treatment.

The prevalence and incidence of metabolic-associated fatty liver disease (MAFLD), a clinically heterogeneous disease whose primary clinical therapies include dietary control and exercise therapy, is increasing worldwide and constitutes a significant medical burden. Gut microbes influence the physiopathological processes of the liver through different mechanisms based on the gut-liver axis. Exosomes are essential carriers of intercellular communication. Most previous studies have focused on adipocyte- and hepatocyte-derived exosomes, while the critical role of microbial-derived exosomes and the molecular mechanisms behind them in MAFLD have received little attention. Therefore, we searched and screened the latest relevant studies in the PubMeb database to elucidate the link between microbial-derived exosomes and the pathogenesis of MAFLD, mainly in terms of insulin resistance, intestinal barrier, inflammatory response, lipid metabolism, and liver fibrosis. The aim was to provide a theoretical framework and support for clinical protocols and innovative drug development.

Trends in innovative drug development in China.

Trends in innovative drug development in China.

Impact of expedited programs in the United States, as foreign regulatory factors, on clinical development time in Japan

Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development. In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs. The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p=0.008), FT (p=0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time. US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

Functional genomics and the future of iPSCs in disease modeling.

SummaryInduced pluripotent stem cells (iPSCs) are valuable in disease modeling because of their potential to expand and differentiate into virtually any cell type and recapitulate key aspects of human biology. Functional genomics are genome-wide studies that aim to discover genotype-phenotype relationships, thereby revealing the impact of human genetic diversity on normal and pathophysiology. In this review, we make the case that human iPSCs (hiPSCs) are a powerful tool for functional genomics, since they provide an in vitro platform for the study of population genetics. We describe cutting-edge tools and strategies now available to researchers, including multi-omics technologies, advances in hiPSC culture techniques, and innovations in drug development. Functional genomics approaches based on hiPSCs hold great promise for advancing drug discovery, disease etiology, and the impact of genetic variation on human biology.

Recent Advances in Application of Computer-Aided Drug Design in Anti-Influenza A Virus Drug Discovery.

Influenza A is an acute respiratory infectious disease caused by the influenza A virus, which seriously threatens global human health and causes substantial economic losses every year. With the emergence of new viral strains, anti-influenza drugs remain the most effective treatment for influenza A. Research on traditional, innovative small-molecule drugs faces many challenges, while computer-aided drug design (CADD) offers opportunities for the rapid and effective development of innovative drugs. This literature review describes the general process of CADD, the viral proteins that play an essential role in the life cycle of the influenza A virus and can be used as therapeutic targets for anti-influenza drugs, and examples of drug screening of viral target proteins by applying the CADD approach. Finally, the main limitations of current CADD strategies in anti-influenza drug discovery and the field’s future directions are discussed.

Promoting Sustainability through Next-Generation Biologics Drug Development

The fourth industrial revolution in 2011 aimed to transform the traditional manufacturing processes. As part of this revolution, disruptive innovations in drug development and data science approaches have the potential to optimize CMC (chemistry, manufacture, and control). The real-time simulation of processes using “digital twins” can maximize efficiency while improving sustainability. As part of this review, we investigate how the World Health Organization’s 17 sustainability goals can apply toward next-generation drug development. We analyze the state-of-the-art laboratory leadership, inclusive personnel recruiting, the latest therapy approaches, and intelligent process automation. We also outline how modern data science techniques and machine tools for CMC help to shorten drug development time, reduce failure rates, and minimize resource usage. Finally, we systematically analyze and compare existing approaches to our experiences with the high-throughput laboratory KIWI-biolab at the TU Berlin. We describe a sustainable business model that accelerates scientific innovations and supports global action toward a sustainable future.

IDF21-0387 Efficacy of Dapagliflozin and Its Role on Microalbuminuria: Multicentric Real World Evidence from Pakistan

Background: Disease progression in diabetes accompany a surge in complications that needs to be tackled. To achieve glycemic goals a comprehensive and effective antidiabetic drug regimen is required. Recent innovations in drug development have provided convenient and effective treatment options with oral agents that have their mode of action targeting both macro and microvascular complications. The Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors are a class of antidiabetic agents that work exclusively independent of insulin action, taking into account only the renal capacity and blood glucose levels.

Trace therapeutic substances of traditional Chinese medicine: great resources of innovative drugs derived from traditional Chinese medicine

The traditional Chinese medicine(TCM) contains very complex constituents. Besides the major constituents, there are a large number of unclear trace constituents with novel skeletons and potent bioactivities, which have been regarded as one of the important therapeutic substances and the great resources of innovative drugs derived from TCM. The present review highlighted that the development of the trace therapeutic substances of TCM is closely depends on the advanced technologies for their identification, isolation, structure elucidation, and bioactivity evaluation. Additionally, this paper reviewed the novel trace compounds derived from Chinese herbal medicines which have been published in Organic Letters during 2001-2021, and summarized the important licensed drugs originated from the trace therapeutic substances and the discovery and development of trace therapeutic substances of 8 kinds of Chinese herbal medicines. This review provides references for the research and development of TCM therapeutic substances and innovative drugs.

Structure and activity of the DHNA Coenzyme-A Thioesterase from Staphylococcus aureus providing insights for innovative drug development

Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria. Within this scenario, Staphylococcus aureus, in particular methicillin resistant S. aureus (MRSA), is responsible for a number of hospital-acquired bacterial infections. The emergence of microbial antibiotic resistance urgently requires the identification of new and innovative strategies to treat antibiotic resistant microorganisms. In this context, structure and function analysis of potential drug targets in metabolic pathways vital for bacteria endurance, such as the vitamin K2 synthesis pathway, becomes interesting. We have solved and refined the crystal structure of the S. aureus DHNA thioesterase (SaDHNA), a key enzyme in the vitamin K2 pathway. The crystallographic structure in combination with small angle X-ray solution scattering data revealed a functional tetramer of SaDHNA. Complementary activity assays of SaDHNA indicated a preference for hydrolysing long acyl chains. Site-directed mutagenesis of SaDHNA confirmed the functional importance of Asp16 and Glu31 for thioesterase activity and substrate binding at the putative active site, respectively. Docking studies were performed and rational designed peptides were synthesized and tested for SaDHNA inhibition activity. The high-resolution structure of SaDHNA and complementary information about substrate binding will support future drug discovery and design investigations to inhibit the vitamin K2 synthesis pathway.

In vitro antioxidant and cytotoxicity activities of selected indigenous South African medicinal plants

Background: Medicinal plants are regarded as a large source of phytochemicals that may have anticancer properties. This could lead to the development of innovative drugs or alternative therapy against cancer.
 Objective: This study was designed to determine the antioxidant and cytotoxicity effect of 5 selected indigenous South African medicinal plants namely; Bulbine frutescens, Bulbine natalensis, Chlorophytum comosum, Kniphofia uvaria, and Tulbaghia violacea.
 Method: Phytochemical extracts namely; methanol, 50%, 100% ethanol, and water extracts were prepared from the root and shoot of the plants. The antioxidant effect of methanol extracts of the plant materials was performed using a DPPH assay. A preliminary cytotoxicity screening of the phytochemical extracts in the human colon (Caco-2), cervical (HeLa), and hepatocellular (HepG2) cell lines were determined followed by the half-maximal inhibitory concentration (IC50) using MTT assay.
 Result: The methanol root extract of B. natalensis and B. frutescens (33.20% and 26.33% respectively) and shoot extract of K. uvaria (17.10%) showed the highest antioxidant. Out of the 5 plants, only 100% ethanol extract of C. comosum, K. uvaria, and T. violacea caused more than 80% cytotoxicity in HepG2 and Caco-2 cell lines. The shoot of B. frutescens (10.43 μg/ml), K. uvaria (23.0 μg/ml), and root of C. comosum (23.77 μg/ml) were the most active with the highest cytotoxicity.
 Conclusion: C. comosum, K. uvaria, and T. violacea possess significant cytotoxicity that is promising in developing alternative drugs against colon and liver cancers. Our results provided new pieces of evidence for antioxidant and cytotoxic activities of these plants which could be useful for developing new anticancer therapies.
 Keywords: In vitro antioxidant; cytotoxicity activities; South African medicinal plants; C. comosum, K. uvaria, T. violacea.

Discovery of exogenous ligands for orphan receptor BRS-3 from Chinese herbs

Bombesin receptor subtype-3(BRS-3) is an orphan receptor in the bombesin receptor family. Its signal transduction mechanism and biological function have attracted much attention. Seeking the ligand for BRS-3 is of great significance for exploring its function. Considering the fact that the activation of BRS-3 receptor can induce the change in intracellular Ca~(2+) concentration, the fluo-rometric imaging plate reader(FLIPR) was utilized for ligand screening at the cellular level. Among more than 400 monomeric compounds isolated from Chinese herbs, yuanhunine from Corydalis Rhizoma and sophoraisoflavanone A and licoriphenone from Glycyrrhizae Radix et Rhizoma antagonized BRS-3 to varying degrees. It was confirmed in HEK293 cells expressing BRS-3 that yuanhunine, sophoraisoflavanone A, and licoriphenone inhibited the calcium current response after the activation of BRS-3 by [D-Phe~6,β-Ala~(11),Phe~(13),Nle~(14)]bombesin-(6-14) in a dose-dependent manner with the IC_(50) values being 8.58, 4.10, and 2.04 μmol·L~(-1), respectively. Further study indicated that yuanhunine and sophoraisoflavanone A exhibited good selectivity for BRS-3. In this study, it was found for the first time that monomers derived from Chinese herbs had antagonistic activity against orphan receptor BRS-3, which has provided a tool for further study of BRS-3 and also the potential lead compounds for new drug discovery. At the same time, it provides reference for the research and development of innovative drugs based on the active ingredients of Chinese herbs.

Kakonein restores hyperglycemia-induced macrophage digestion dysfunction through regulation of cathepsin B-dependent NLRP3 inflammasome activation.

In hyperglycemia‐induced complications, macrophages play important roles in disease progression, and altered digestion is a key feature that dictates macrophage function. Recent evidence indicates that kakonein (Ka) possesses anti‐inflammatory activities for hyperglycemia‐induced complication. In this study, we established a mouse model of Nlrp3+/+ and Nlrp3−/− hyperglycemia and administering Ka, primary culture macrophages were tested by engulfing and digesting microbes. The role of macrophages in the cathepsin B–NLRP3 pathway involved in the mechanism of Ka in restoring macrophage digestion function was investigated using biochemical analyses, molecular biotechnology, and microbiology. Ka restored the function of macrophage digestion, which were same characterized by Nlrp3−/− mice. Meanwhile, kakonein could decrease NLRP3 inflammasome products expression and NLRP3/ASC or NLRP3/Casp1 colocalization in macrophage. Interestingly, Ka suppressed inflammasome response not by reducing NLRP3 and ASC expression but by reducing cathepsin B release and activation. And Ka restored macrophage digestion and inhibited NLRP3 inflammasome activation consistent with cathepsin B inhibitor. It is concluded that Ka reduced the release of lysosomal cathepsin B and consequently inhibited NLRP3 inflammasome activation to prevent macrophage digestion. Hence, Ka may contribute to new targets for treatment of hyperglycemia‐associated dysfunction of macrophage digestion and development of innovative drugs.

Gold Nanoparticle-Based Photo-Cross-Linking Strategy for Cellular Target Identification of Supercomplex Molecular Systems.

Cellular target identification plays an essential role in innovative drug development and pharmacological mechanism elucidation. However, very few practical experimental methodologies have been developed for identifying target proteins for supercomplex molecular systems such as biologically active phytochemicals or pharmaceutical compositions. To overcome this limitation, we synthesized gold nanoparticles (AuNPs) as solid scaffolds, which were bound with 4,4'-dihydroxybenzophenone (DHBP) as a photo-cross-linking group on the surface. Then, DHBP-modified AuNPs cross-linked various organic compounds from phytochemicals under ultraviolet radiation via carbene reactions, H-C bond insertion, for catalytic C-C bond formation. We next used the phytochemical-cross-linked AuNPs (phytoAuNPs) to pull down potential binding proteins from brain tissue lysate and identified 13 neuroprotective targets by mass spectrometry analysis. As an exemplary study, we selected Hsp60 as a crucial cellular target to further screen 14 target-binding compounds from phytochemicals through surface plasmon resonance (SPR) analysis, followed by Hsp60 activity detection and neuroprotective effect assay in cells. Collectively, this gold nanoparticle-based photo-cross-linking strategy can serve as a useful platform for discovering novel cellular targets for supercomplex molecular systems and help to explore pharmacological mechanisms and active substances.

Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic. In particular, late-onset AD possesses a clear metabolic signature. Considerable brain insulin signaling impairment and a decline in glucose metabolism are common AD attributes. Thus, positron emission tomography (PET) with glucose tracers is a reliable non-invasive tool for early AD diagnosis and treatment efficacy monitoring. Various approaches and agents have been trialed to modulate insulin signaling. Accumulating data point to arginase inhibition as a promising direction to treat AD via diverse molecular mechanisms involving, inter alia, the insulin pathway. Here, we use a transgenic AD mouse model, demonstrating age-dependent brain insulin signaling abnormalities, reduced brain insulin receptor levels, and substantial energy metabolism alterations, to evaluate the effects of arginase inhibition with Norvaline on glucose metabolism. We utilize fluorodeoxyglucose whole-body micro-PET to reveal a significant treatment-associated increase in glucose uptake by the brain tissue in-vivo. Additionally, we apply advanced molecular biology and bioinformatics methods to explore the mechanisms underlying the effects of Norvaline on glucose metabolism. We demonstrate that treatment-associated improvement in glucose utilization is followed by significantly elevated levels of insulin receptor and glucose transporter-3 expression in the mice hippocampi. Additionally, Norvaline diminishes the rate of Tau protein phosphorylation. Our results suggest that Norvaline interferes with AD pathogenesis. These findings open new avenues for clinical evaluation and innovative drug development.

Immobilization of peroxisome proliferator-activated receptor gamma and the application in screening modulators of the receptor from herbal medicine

Screening and identification of potential compounds from herbal medicine is a prevailing way to find a lead for the development of innovative drugs. This promotes the development of new methods that are feasible in complex matrices. Here, we described a one-step reversible methodology to immobilize nuclear peroxisome proliferator-activated receptor gamma (PPARγ) onto amino microsphere coated with a DNA strand specifically binding to the receptor. The specific interaction allowed us to achieve the immobilization of PPARγ by mixing the DNA modified microspheres with E. coli lysates expressing the receptor. Characterization of the immobilized receptor was carried out by morphology and binding specificity analysis. Feasibility of immobilized PPARγ in the drug-receptor interaction analysis was performed by an injection amount-dependent method. Besides, immobilized PPARγ was also applied in screening modulators of the receptor from Coptidis Rhizoma extract. The binding of the screened compounds to PPARγ was examined by time-resolved fluorescence resonance energy transfer assay. The results showed that immobilized PPARγ was stable for thirty days with a high-specificity of ligand recognition at the subtype receptor level. Berberine and palmatine were the bioactive compounds of Coptidis Rhizoma specifically binding to PPARγ. The two compounds exhibited half maximal inhibitory concentrations of 4.11 and 2.98 μM during their binding to the receptor. We concluded that the current method is possible to become a common strategy for the immobilization of nuclear receptors, and the immobilized receptor is a high throughput method for recognizing and separating the receptor modulators from complex matrices including herbal medicine.