Development Of Innovative Drugs Research Articles

Autoantibodies in Myasthenia Gravis

Myasthenia gravis (MG) is one of the autoantibody-mediated neuroimmunological diseases. Autoantibodies to the muscle-type nicotinic acetylcholine receptor (AChR) were detected in more than 80% of MG patients. The gene structure and pathogenicity of some AChR antibodies produced in MG have already been identified and elucidated, respectively. Therefore, the AChR antibody is similar in nature to innovative drug development targets with respect to MG treatment. Here, we discuss the development of molecular target drugs for AChR antibody-positive MG.

The structure of FIV reverse transcriptase and its implications for non-nucleoside inhibitor resistance.

Reverse transcriptase (RT) is the target for the majority of anti-HIV-1 drugs. As with all anti-AIDS treatments, continued success of RT inhibitors is persistently disrupted by the occurrence of resistance mutations. To explore latent resistance mechanisms potentially accessible to therapeutically challenged HIV-1 viruses, we examined RT from the related feline immunodeficiency virus (FIV). FIV closely parallels HIV-1 in its replication and pathogenicity, however, is resistant to all non-nucleoside inhibitors (NNRTI). The intrinsic resistance of FIV RT is particularly interesting since FIV harbors the Y181 and Y188 sensitivity residues absent in both HIV-2 and SIV. Unlike RT from HIV-2 or SIV, previous efforts have failed to make FIV RT susceptible to NNRTIs concluding that the structure or flexibility of the feline enzyme must be profoundly different. We report the first crystal structure of FIV RT and, being the first structure of an RT from a non-primate lentivirus, enrich the structural and species repertoires available for RT. The structure demonstrates that while the NNRTI binding pocket is conserved, minor subtleties at the entryway can render the FIV RT pocket more restricted and unfavorable for effective NNRTI binding. Measuring NNRTI binding affinity to FIV RT shows that the “closed” pocket configuration inhibits NNRTI binding. Mutating the loop residues rimming the entryway of FIV RT pocket allows for NNRTI binding, however, it does not confer sensitivity to these inhibitors. This reveals a further layer of resistance caused by inherent FIV RT variances that could have enhanced the dissociation of bound inhibitors, or, perhaps, modulated protein plasticity to overcome inhibitory effects of bound NNRTIs. The more “closed” conformation of FIV RT pocket can provide a template for the development of innovative drugs that could unlock the constrained pocket, and the resilient mutant version of the enzyme can offer a fresh model for the study of NNRTI-resistance mechanisms overlooked in HIV-1.

Regulatory Science – An Underappreciated Component of Translational Research

Translational science refers to translating basic scientific findings to practical application (i.e., 'bench-to-bedside'). An underappreciated aspect of translational science is regulatory science. Herein, we focus on the importance of regulatory science to facilitate development of innovative new drugs and optimize use of approved drugs, with a call for community participation.

Tacrine-deferiprone hybrids as multi-target-directed metal chelators against Alzheimer's disease: a two-in-one drug.

Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting several million people worldwide. So far, there is no adequate medication to prevent or slow down the progression of the disease, only medication with palliative effects allowing temporary symptomatic reliefs. As part of our continuing efforts into the development of innovative drugs following a polypharmacological strategy, we decided to use a former anti-AD palliative drug (tacrine) and to reposition it by hybridization with a metal chelating drug (deferiprone, DFP). This combination endows the hybrids with good capacity to inhibit acetylcholinesterase (low micromolar range) and self-/Cu-induced Aβ aggregation (up to ca. 90%) as well as a good radical scavenging ability (micromolar range) and metal (M) chelating capacity, with pM (pM = -log[M], CL/CM = 10, CM = 10-6 M at pH = 7.4, M = Fe, Cu, Zn) values close to those of DFP. The most promising compounds have 2-hydroxypropyl linkers, and a selection of compounds have demonstrated neuroprotective roles in neuroblastoma cells treated with Aβ1-42 and ascorbate/iron stressors. Consequently, these hybrids can be considered as attractive multipotent therapeutic molecules that will eventually play key roles against AD progression, namely in the control of cholinergic dysfunction, amyloid peptide aggregation, oxidative stress, and metal modulation, besides presenting a good pharmacokinetic profile.

Current Readings: An Update on Prevention and Management of Atrial Fibrillation Post Cardiac Surgery

Atrial fibrillation (afib) remains the most common complication following cardiac surgery and is associated with increased mortality and resource utilization. As increasing number of patients with multiple comorbidities undergo cardiac surgery, and, given the overall burden of afib in the perioperative setting, there is growing interest among clinicians to improve diagnosis and management of afib among cardiac surgery patients. Advances in technology, refinements in surgical techniques, and innovations in drug development also contributed to this changing landscape. Despite the promising results of recently published studies on afib management following cardiac surgery, afib remains a complex problem with various presentations. Although myriad medical and surgical therapies for high-risk patients exist, determining patient-specific optimal treatment can be difficult. Understanding the context and relevance of contemporary studies is therefore critical to ensure appropriate patient selection and reduction of overall morbidity and mortality. This review closely examines 5 timely articles that delineate the most important results in the management of afib after cardiac surgery in the current era.

Innovations in drug development through transcriptomic analysis of liquid biopsies and exosome utility

Innovations in drug development through transcriptomic analysis of liquid biopsies and exosome utility

Accessible Metabolites from Siberian Plants for Development and Production of Innovative Drugs

Accessible Metabolites from Siberian Plants for Development and Production of Innovative Drugs

Implementation of a Market Entry Reward within the United States.

As part of a multifactorial approach to address weak incentives for innovative antimicrobial drug development, market entry rewards (MERs) are an emerging solution. Recently, the Duke-Margolis Center for Health Policy released the Priority Antimicrobial Value and Entry (PAVE) Award proposal, which combines a MER with payment reforms, transitioning from volume-based to "value-based" payments for antimicrobials. Here, the PAVE Award and similar MERs are reviewed, focusing on further refinement and avenues for implementation.

Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development.

Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.

NOP Ligands for the Treatment of Anxiety and Mood Disorders.

Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating anxiety- and mood-related disorders. Evidence supports the view that the activation of NOP receptors with agonists elicits anxiolytic-like effects, while its blockade with NOP antagonists promotes antidepressant-like actions in rodents. Genetic studies showed that NOP receptor knockout mice display an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. In contrast, the genetic blockade of NOP receptor signaling generally displays an increase of anxiety states in the elevated plus-maze test. In this chapter we summarized the most relevant findings of NOP receptor ligands in the modulation of anxiety and mood disorders, and the putative mechanisms of action are discussed.

How can we contribute to innovative drug development? ～From our experience in participating global study

How can we contribute to innovative drug development? ～From our experience in participating global study

Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents.

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm with no specific line of differentiation. Eribulin, a novel synthetic microtubule inhibitor, has shown anticancer activity in several tumors, including soft tissue sarcomas (STS). We investigated the molecular biology of UPS, and the mechanisms of action of this innovative microtubule-depolymerizing drug. A primary culture from a patient with UPS was established and characterized in terms of gene expression. The activity of eribulin was also compared with that of other drugs currently used for STS treatment, including trabectedin. Finally, Western blot analysis was performed to better elucidate the activity of eribulin. Our results showed an upregulation of epithelial mesenchymal transition-related genes, and a downregulation of epithelial markers. Furthermore, genes involved in chemoresistance were upregulated. Pharmacological analysis confirmed limited sensitivity to chemotherapy. Interestingly, eribulin exhibited a similar activity to that of standard treatments. Molecular analysis revealed the expression of cell cycle arrest-related and pro-apoptotic-related proteins. These findings are suggestive of aggressive behavior in UPS. Furthermore, the identification of chemoresistance-related genes could facilitate the development of innovative drugs to improve patient outcome. Overall, the results from the present study furnish a rationale for elucidating the role of eribulin for the treatment of UPS.

Development and application of component-based Chinese medicine theory

Traditional Chinese medicine (TCM) prescription is the main therapies for disease prevention and treatment in Chinese medicine. Following the guidance of the theory of TCM and developing drug by composing prescriptions of TCM materials and pieces, it is a traditional application mode of TCM, and still widely used in clinic. TCM prescription has theoretical advantages and rich clinical application experience in dealing with multi-factor complex diseases, but scientific research is relatively weak. The lack of scientific cognition of the effective substances and mechanism of Chinese medicine leads to insufficient understanding of the efficacy regularity, which affects the stability of effect and hinders the improvement of quality of Chinese medicinal products. Component-based Chinese medicine (CCM) is an innovation based on inheritance, which breaks through the tradition of experience-based prescription and realize the transformation of compatibility from herbal pieces to components. CCM is an important achievement during the research process of modernization of Chinese medicine. Under the support of three national "973" projects, in order to reveal the scientific connotation of the prescription compatibility theory and develop innovative Chinese drugs, we have launched theoretical innovation and technological innovation around the "two relatively clear", and opened up the research field of CCM. CCM is an innovation based on inheritance, breaking through the tradition of experience based prescription, and realizing the transformation from compatibility of herbal pieces to component compatibility, which is an important achievement of the modernization of traditional Chinese medicine. In the past more than 10 years, with the deepening of research and the expansion of application, the theory and methods of CCM and efficacy-oriented compatibility have been continuously improved. The value of CCM is not only in developing new drug, more important is to build a communication bridge between traditional Chinese medicine and modern science and construct the system of key technologies which meet the need of innovation and development of TCM. This paper focused on the research progress, related concepts and technology development of CCM, as well as its application prospect in the theory research of Chinese medicine, development of innovative Chinese drugs, secondary development of Chinese patent medicine and upgrading of pharmaceutical technology.

New Insights for the Use of Quercetin Analogs in Cancer Treatment

Quercetin (Q1) is a flavonoid widely present in plants and endowed with several pharmacological properties mostly due to its antioxidant potential. Q1 shows anticancer activity and could be useful in cancer prevention. On the other hand, Q1 is poorly soluble in water and unstable in physiological systems, and its bioavailability is very low. A small set of Q1 derivatives (Q2-Q9) has been synthesized following opportunely modified chemical procedures previously reported. Anticancer activity has been evaluated by MTT assay. Human Topoisomerases inhibition has been performed by direct enzymatic assays. Apoptosis has been evaluated by TUNEL assay. ROS production and scavenging activity have been determined by immunofluorescence. The anticancer profile of a small library of Q1 analogues, in which the OH groups were all or partially replaced with hydrophobic functional groups, has been evaluated. Two of the studied compounds demonstrated an interesting cytotoxic profile in two breast cancer models showing the capability to inhibit human Topoisomerases. The studied compounds represent suitable leads for the development of innovative anticancer drugs. [Formula: see text].

Insights into the interactions between corrinoid iron-sulfur protein and methyl transferase from human pathogen Clostridium difficile

The human pathogen Clostridium difficile infection(CDI) is one of the most important healthcare-associated infections. Methyltransferase(MeTrCd) and corrinoid iron-sulfur protein(CoFeSPCd) are two key proteins in the acetyl-coenzyme A synthesis pathway of Clostridium difficile, which is essential for the survival of the pathogen and is absent in humans. Hence, the interaction between MeTrCd and CoFeSPCd can become innovative targets for the treatment of human CDI. In this study, the interaction between MeTrCd and CoFeSPCd was verified by fluorescence resonance energy transfer measurements. The influence of the interaction on the tertiary structure of MeTrCd and CoFeSPCd was studied by ANS-labeled fluorescence measurements. Molecular docking was also performed to understand the mechanism of the protein interactions. These results provide a molecular basis for innovative drug design and development to treat human CDI.

Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems.

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century.

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I.

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.

Abstract 1840: Whole-exome somatic mutation analysis of mouse cancer models and implications for preclinical immunomodulatory drug development

Abstract Experimental tumors raised in rodents represent an important preclinical tool to develop innovative anticancer compounds before clinical testing. Amongst others such models include solid tumors raised in syngeneic fully immunocompetent hosts and tumors spontaneously growing in genetically engineered mice (GEM) and derivate thereof. These model platforms have gained additional value since the manipulation of the immune system to fight cancer has led to tangible benefits for cancer patients. In the current study, we analyzed somatic mutation profiles from whole-exome sequencing (WES) data in a panel of 14 different mouse models covering 6 major cancer types. 4 models were GEM-derived, all other lines were developed by injection of established cell lines into the corresponding mouse strain. In parallel, these models were evaluated for their sensitivity towards checkpoint inhibitors (α-CTLA-4, α-PD-1 or α-PDL-1) in mono- or combined therapy with cytostatic and/or targeted agents.WES achieved an average-of-coverage of 165X in tumor models and normal DNA. A median mutation rate of 34 somatic mutations (m)/MB was detected, ranging from 7 m/MB (GEM derived NSCLC model KP) to 328 m/MB (syngeneic NSCLC line Lewis Lung) in exons. Mutation rates were markedly lower in GEM-derived models as in syngeneic lines (median of 9 vs 43 m/MB). This reflects very well the different underlying carcinogenic mechanism of these two types of models. The cross-comparison of tissue-transplants vs cell lines from GEM-derived model KP revealed that 75% of the mutations found in the primary KP could also be detected in the corresponding cell lines KP1 and KP4. Of note, the mutation count increased 1.3- (KP4) and 2.9-fold (KP1) during cell line establishment. Every model depicted a distinct profile against modulators of the immune system dividing the panel in responders and non-responders. In our hands no significant correlation could be determined between mutational load and sensitivity towards checkpoint inhibition in vivo. This might be related to the fact that the dataset was not broad enough and the number of models per entity was too small, rendering the subtype analysis within the panel not feasible. However, a strong tendency was observed when investigating the colon lines Colon26, CT26 and MC38 showing best response to the combination of PD-1+CTLA-4 inhibitors and in parallel the highest mutation rates (52, 64 and 59 m/MB, respectively) compared to non-responders B16-F10, CloudmanS91, 4T1 and KP1 (23 m/MB on average). Mouse models of cancer are a relevant tool for preclinical studies specifically for immuno-oncology. The molecular characterization of these models will help to optimize their use in drug discovery. They will support the development of innovative drugs and indentification of biomarkers to classify the patient cohort profiting the most from these new compounds. Citation Format: Bruno Zeitouni, Cordula Tschuch, Jason M. Davis, Anne-Lise Peille, Yana Raeva, Manuel Landesfeind, Sheri Barnes, Julia B. Schüler. Whole-exome somatic mutation analysis of mouse cancer models and implications for preclinical immunomodulatory drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1840. doi:10.1158/1538-7445.AM2017-1840

AGC kinases, mechanisms of regulation ‎and innovative drug development.

The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases.

Progress on treatment of rheumatoid arthritis with ethnodrugs

Rheumatoid arthritis(RA) is a chronic autoimmune disease, belonging to the "Arthromyodynia (Bi Zheng)" category in traditional Chinese medicine. However, the ethnomedicine has a unique understanding of RA, with a long-term clinical experience accumulation and significant efficacy in the treatment of RA, and it has now become one of the important means in treatment of RA. On the basis of literature research, the understanding of RA and commonly used Tibetan medicine, Mongolian medicine, Hui medicine and other herbs and preparations were reviewed in this paper, with the aim of providing a reference for its clinical treatment of RA and research and development of innovative drugs.