Drug Development Technologies Research Articles

Tailoring epilepsy treatment: personalized micro-physiological systems illuminate individual drug responses

Introduction: Approximately 50 million people worldwide have epilepsy, with many not achieving seizure freedom. Organ-on-chip technology, which mimics organ-level physiology, could revolutionize drug development for epilepsy by replacing animal models in preclinical studies. The authors’ goal is to determine if customized micro-physiological systems can lead to tailored drug treatments for epileptic patients. Materials and methods: A comprehensive literature search was conducted utilizing various databases, including PubMed, Ebscohost, Medline, and the National Library of Medicine, using a predetermined search strategy. The authors focused on articles that addressed the role of personalized micro-physiological systems in individual drug responses and articles that discussed different types of epilepsy, diagnosis, and current treatment options. Additionally, articles that explored the components and design considerations of micro-physiological systems were reviewed to identify challenges and opportunities in drug development for challenging epilepsy cases. Results: The micro-physiological system offers a more accurate and cost-effective alternative to traditional models for assessing drug effects, toxicities, and disease mechanisms. Nevertheless, designing patient-specific models presents critical considerations, including the integration of analytical biosensors and patient-derived cells, while addressing regulatory, material, and biological complexities. Material selection, standardization, integration of vascular systems, cost efficiency, real-time monitoring, and ethical considerations are also crucial to the successful use of this technology in drug development. Conclusion: The future of organ-on-chip technology holds great promise, with the potential to integrate artificial intelligence and machine learning for personalized treatment of epileptic patients.

Abstract 4712: GPCR panel establishment and application in drug discovery

Abstract G protein-coupled receptors (GPCRS) are the largest family of membrane proteins of cell surface receptors. It can be activated by various stimuli and play an important role in various physiological and pathological processes such as cell growth, proliferation, differentiation, metabolism, and homeostasis. Abnormal regulation of GPCR is associated with various human diseases, such as metabolic diseases, cardiovascular diseases, and eye diseases. G protein contains three subunits: α, β, and γ, which form a trimer. When extracellular ligands are bound to GPCRs which activate G protein and GTP phosphorylates Gα subunits, leading to the dissociation of Gα subunits from the trimer and dissociation from the β and γ subunits. In addition, Gα different subtypes of Gαs, Gαi and Gαq have different biological effects after activation, Gas-coupled receptors activate adenylyl cyclase (AC) to increase cAMP. In contrast, Gαi-coupled receptors activated adenylyl cyclase (AC) to inhibit cAMP. Gαq coupled receptors promote phospholipase C (PLC) to produce IP3, and IP3 can increase intracellular Ca2+ concentration. GPCR Panel With high general availability, which provides over 150 GPCR targets, covering wide families like 5-Hydroxytryptamine, adrenoceptors, Acetylcholine, dopamine, glucagon, and opioid receptors and having the selectivity of multiple species. It can conduct similar GPCR poly-link interaction and screening, used to study new GPCR drug development technology, detect the expression properties of GPCR receptors, reveal new GPCR structure and function, and screen GPCR drugs. We also constructed different assay platforms, including cAMP assay, Ca2+ flux assay, IP3 assay, β-arrestin recruitment assay and reporter assay to detect the different second messengers produced by G protein submits and GPCR-mediated multiple signaling pathways. This research constructed stable cell lines expressing GPCRs and provided related assays, which could be used to detect compounds' effects on GPCR targets successfully. In addition, the GPCR panel was applicable to both activating and inhibitory models, and the establishment of this platform provides a powerful tool for drug development of GPCR-related targets. Citation Format: Xiaoyan Wang, Ning Sui, Dandan Hu, Ziwei Zhang, Tiejun Bing. GPCR panel establishment and application in drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4712.

Programmed aptamer target chain reaction (ATCR) for smart therapeutic inhibitor development

Drug misdosing is a common cause of adverse effects. We first developed an aptamer target chain reaction (ATCR), which relies on a bivalent aptamer (HDTB-2) engineered with a sufficiently short spacer to continuously bind the target molecules, subsequently forming an aptamer target chain (ATC). ATCR is an universal, size-tunable, highly controllable, isothermal, self-assembly, and enzyme-free method for biomaterial formation. Through selecting aptamers with appropriate binding affinities, HDTB-2 inhibits target molecules only at the upregulated level and keeps it free at a healthy level to minimize the side effects due to misdosing. The design is applied as a smart anticoagulant, which exhibited stronger protection against misdosing and inhibition effects than commercial anticoagulants, due to the effective binding and enclosure of target molecules induced by the formation of bulky ATC. The efficacy and exceptional side effect management capability were further validated by a series of in vitro and in vivo experiments. To the best of our knowledge, this is the first report of a universal, non-covalently linked nucleic acid-biomolecule chain self-assembly method and a drug development technology that equips active pharmaceutical ingredients (API) with self-regulatory capability for smart management of the side effects.

Analysis of the Fifth Set of listing standards of China Science and Technology Innovation Board

With the landing of micro-electrophysiology on the Science and Technology Innovation Board, the fifth set of Science and Technology Innovation Board listing rules appeared and hoped to promote the development of new things in domestic capital production. The fifth set of Science and Technology Innovation Board listing rules reflects the inclusiveness of the Science and Technology Innovation Board because this set of listing rules is for some unprofitable or small-profit research and development technology, innovation, and future development of enterprises listed standards. Including the core technology, production products and stage results, good market trends, and innovative technological advantages. Especially for most types of biological drug development or medical technology companies. Today, almost all the companies that use the fifth set of Science and Technology Innovation Board to go public have commercialized their products, gained operating income of 100 million yuan, and some companies have even earned profits. As time goes on, the fifth set of Science and Technology Innovation Board of the development is getting better and better. There are many successful cases for other companies with the same enterprises to reference, and the future trend is also on the rise. However, due to the special characteristics of the Technology Innovation Board, the liberalization of IPO listing also brings great risks to the auditing work.

Enhanced Tumor Targeting and Penetration of Proteolysis-Targeting Chimeras through iRGD Peptide Conjugation: A Strategy for Precise Protein Degradation in Breast Cancer.

Proteolysis-targeting chimeras (PROTACs) have recently emerged as a promising technology for drug development. However, poor water solubility, limited tissue selectivity, and inadequate tumor penetration pose significant challenges for PROTAC-based therapies in cancer treatment. Herein, we developed an iRGD-PROTAC conjugation strategy utilizing tumor-penetrating cyclic peptide iRGD (CRGDK/RGPD/EC) to deliver PROTACs deep into breast cancer tissues. As a conceptual validation study, iRGD peptides were conjugated with a bromodomain-containing protein 4 (BRD4) PROTAC through a GSH-responsive linker. The resulting iRGD-PROTAC conjugate iPR showed enhanced water solubility, tumor-targeting capability, and penetration within tumor tissues, resulting in increased antibreast cancer efficacy in animal models and patient-derived organoids. This study demonstrates the advantages of combining iRGD and PROTACs in improving drug delivery and highlights the importance of tissue selectivity and penetration ability in PROTAC-based therapeutics.

Advancements in virtual screening techniques for study of enzyme inhibitor compounds

Enzymes are closely associated with the onset and progression of numerous diseases, making enzymes a primary target in innovative drug development. However, the challenge remains in identifying compounds that exhibit potent inhibitory effects on the target enzymes. With the continuous expansion of the total number of natural products and increasing difficulty in isolating and enriching new compounds, traditional high-throughput screening methods are finding it increasingly challenging to meet the demands of new drug development. Virtual screening, characterized by its high efficiency and low cost, has gradually become an indispensable technology in drug development. It represents a prominent example of the integration of artificial intelligence with biopharmaceuticals and is an inevitable trend in the rapid development of innovative drug screening in the future. Therefore, this article primarily focused on systematically reviewing the recent applications of virtual screening technology in the development of enzyme inhibitors and explored the prospects and advantages of using this technology in developing new drugs, aiming to provide essential theoretical insights and references for the application of related technologies in the field of new drug development.

Drug Delivery to the Brain: Recent Advances and Unmet Challenges.

Brain cancers and neurodegenerative diseases are on the rise, treatments for central nervous system (CNS) diseases remain limited. Despite the significant advancement in drug development technology with emerging biopharmaceuticals like gene therapy or recombinant protein, the clinical translational rate of such biopharmaceuticals to treat CNS disease is extremely poor. The blood-brain barrier (BBB), which separates the brain from blood and protects the CNS microenvironment to maintain essential neuronal functions, poses the greatest challenge for CNS drug delivery. Many strategies have been developed over the years which include local disruption of BBB via physical and chemical methods, and drug transport across BBB via transcytosis by targeting some endogenous proteins expressed on brain-capillary. Drug delivery to brain is an ever-evolving topic, although there were multiple review articles in literature, an update is warranted due to continued growth and new innovations of research on this topic. Thus, this review is an attempt to highlight the recent strategies employed to overcome challenges of CNS drug delivery while emphasizing the necessity of investing more efforts in CNS drug delivery technologies parallel to drug development.

Diagnostic and Therapeutic Application of Proteomics in Infectious Disease

The study of an organism’s genome, often known as “genomics,” has advanced quickly, producing a wealth of publicly accessible genetic data. Despite how valuable the genome is; proteins essentially control most aspects of cell function. Proteomics, or the comprehensive study of proteins, has emerged as an important technology for disease characterization, diagnosis, prognosis, drug development, and therapy. Proteomics technologies are now used to support the diagnosis and treatment of both infectious and noninfectious diseases. Nevertheless, it is more difficult to describe a proteomic profile since a single gene product may result in a number of unique proteins, and proteins have a wider range of chemical configurations. The proteome profiles of a particular organism, tissue, or cell are impacted by a variety of environmental factors, including those triggered by infectious agents. This review intends to highlight the applications of proteomics in the study of disease diagnosis and treatment. In this review, the different technologies used in proteomics studies, like two-dimensional gel electrophoresis, mass spectrometry, and protein microarray as well as biomarker discovery and drug target identification using proteomics, have also been focused on.

Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development.

With the continuous development of the pharmaceutical industry, people have always paid attention to the safety and effectiveness of drugs, including innovative drugs and generic drugs. For pharmaceutical companies as manufacturers, drug development is a very lengthy process that requires high costs, millions of man-hours, thousands of trials, and the mobilization of hundreds of researchers. Therefore, efforts need to be made to develop drugs with high safety and effectiveness. Drug research and development plays an important role today. Based on this, this article applied computer molecular simulation embedded technology and artificial intelligence technology to drug research and development. First, the problems faced in the research and development of anti-inflammatory disease-dependent tumor drugs were introduced, and then the applications of computer molecular simulation embedded technology and artificial intelligence technology in drug research and development were analyzed. Subsequently, the application of artificial intelligence in drug research and development teaching was analyzed, and a teaching system based on computer molecular simulation embedded technology and artificial intelligence was designed. Finally, the application effects of computer molecular simulation embedded technology and artificial intelligence technology were analyzed, and a feasible conclusion was drawn. The use of computer molecular simulation embedded technology and artificial intelligence technology can greatly improve the efficiency of drug research and development, and the research and development safety of imatinib mesylate has been improved by 7%. On the other hand, it can improve students' learning interest and stimulate their learning interest, and students' drug research and development capabilities have been improved. Drug research and development for inflammatory-dependent tumors has good application prospects.

Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs.

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.

Rosalind Franklin Society Proudly Announces the 2022 Award Recipient for Assay and Drug Development Technologies.

Rosalind Franklin Society Proudly Announces the 2022 Award Recipient for Assay and Drug Development Technologies.

Virtual Development of COVID-19 Drugs Targeting Nsp16-Nsp10 Complex

The search for pharmaceutical treatment for COVID-19 has been progressive. Currently approved medicines include therapeutic antibodies and antiviral drugs. However, the effectiveness of current antiviral drugs is far from satisfactory, which suggests the necessity for improvement. In this research, we selected the non-structural protein complex Nsp16-Nsp10, which is responsible for methylating SARS-CoV-2’s RNA, as a drug target. With computer-aided drug development technology, we screened two potential drugs either by inhibiting the SAM catalytic pocket on the complex or inhibiting the binding between Nsp16 and Nsp10 from preventing the Nsp16-Nsp10 complex helping SARS-CoV-2 duplicate, and that will work in COVID-19 treatment.

PROTACs: A novel strategy for cancer drug discovery and development.

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PROTAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PROTAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

Modality diversification and best-in-class small-molecule drugs: Recent trend of orphan drug development

Only 5% of orphan diseases have approved drugs, leading to a high demand for new treatment. As a result, pharmaceutical companies have shifted their focus of drug development to orphan diseases. This study conducted a database search to analyze the modality and development strategy of orphan drugs approved by the Food and Drug Administration from 2011 to 2022. The analysis showed that the modalities used for orphan drugs have diversified with increasing emergence of nucleic acid drugs, gene therapies, cell therapies, antibody drugs including next-generation antibodies, and engineered proteins, suggesting that modality diversification enhances the drug development for orphan diseases that are otherwise challenging to treat with conventional drugs. The ratio of orphan drugs targeting only a single disease has increased, likely due to the emergence of gene-specific treatments such as nucleic acid drugs and gene therapies. Moreover, this study found that orphan drugs using different modalities have been competitively developed with the same mechanism of action targeting only a single orphan disease in recent years. In several cases, small-molecule drugs with unique characteristics offer advantages such as dosing convenience and non-genetic patient coverage over nucleic acid drugs, antibody drugs, and gene therapy. These trends suggest the importance of modality technology development and advancement of small molecule optimization technology for future orphan drug development.

Research progress on genome-guided precision oncology and development ideas of antitumor Chinese medicine

Genome-guided oncology refers to a new treatment concept that transcends histological classification and pathological ty-ping and uses drugs according to the genetic characteristics of tumors. New drug development technology and clinical trial design based on this concept provide new ideas for the clinical application of precision oncology. The multi-component and multi-target characteristics of Chinese medicine provide rich resources for the development of tumor-targeting drugs from natural products, and the design of the master protocol trial aiming at the characteristics of precision oncology supports the rapid clinical screening of effective tumor-targeting drugs. The emergence of the synthetic lethality strategy breaks through the bottleneck that the drug can only target the oncogene but cannot do anything to the tumor suppressor gene with the loss-of-function mutation in the past. With the rapid development of high-throughput sequencing technology, the cost of sequencing is also decreasing. For the development of tumor-targeting drugs, how to keep up with the update speed of target information is a difficult problem of concern. Based on the integration of innovative ideas and me-thods of precision oncology, network pharmacology, and synthetic lethality strategy on synthetic lethal interaction network of antitumor Chinese medicine compatibility formula design, and the combination of improvement of innovative clinical trial methods, such as master protocol trial, basket trial, and umbrella trial, unique advantages of Chinese medicine are expected to be exerted beyond the antibody-based drugs and small molecule-based drugs and corresponding targeted drugs are potentially developed for clinical application.

88P Evaluation of trending drug targets and technologies in current drug development

88P Evaluation of trending drug targets and technologies in current drug development

The urgent need for innovation in contraception.

Despite advancements in medicine over the past decades, there exists a significant unmet global need for new and improved contraceptive methods for men and women. The development of innovative contraceptives will be facilitated via advancements in biomedical science, biomedical engineering, and drug development technologies. This article describes the need for new methods, opportunities afforded by advancements in biomedical science, strategies being employed to advance innovative novel methods, value of drug development accelerators and the need for industry involvement to provide men and women worldwide greater reproductive autonomy.

TPGS-chitosan conjugated mucoadhesive micelles of brinzolamide for glaucoma therapy: In vitro and in vivo evaluation

Micelle is a promising avenue for ophthalmic drug development technology and an especially suitable choice for hydrophobic drugs. The aim of this investigation was to synthesize Brinzolamide (BRZ) loaded d-alpha-tocopherol polyethylene glycol succinate (TPGS) - Chitosan conjugated micelles (BTCM) prepared by solvent evaporation method and to investigate their intraocular pressure (IOP) reducing efficacy for the management of glaucoma. The formulated BTCM was evaluated with various parameters such as size, zeta potential, morphology, percentage drug entrapment efficiency, drug loading capacity, and mucoadhesion strength, in-vitro and ex-vivo release. In-vivo anti-glaucoma efficacy study was conducted by glucocorticoid-induced glaucoma rabbit eye model and evaluated with the Marketed formulation (MF). The optimized formula showed a micelle size of 74.32±1.46 nm, and suitable physicochemical properties and in-vitro release mechanism were observed in that biphasic erosion-diffusion pattern of BRZ releases up to 8 h. The Ex-vivo corneal penetration of BRZ from BTCM showed a higher permeability rate than MF. Additionally, BTCM showed sustained release of BRZ, better corneal tissue compatibility, and improved anti-glaucoma potential, as compared to MF. The results concluded that BTCM is the suitable option for anti-glaucoma therapy because of its capability to improve ocular mucoadhesion of loaded BRZ via the interaction with the mucous membrane of the corneal surface.

Organ-on-a-chip technologies for biomedical research and drug development: A focus on the vasculature.

Current biomedical models fail to replicate the complexity of human biology. Consequently, almost 90% of drug candidates fail during clinical trials after decades of research and billions of investments in drug development. Despite their physiological similarities, animal models often misrepresent human responses, and instead, trigger ethical and societal debates regarding their use. The overall aim across regulatory entities worldwide is to replace, reduce, and refine the use of animal experimentation, a concept known as the Three Rs principle. In response, researchers develop experimental alternatives to improve the biological relevance of in vitro models through interdisciplinary approaches. This article highlights the emerging organ-on-a-chip technologies, also known as microphysiological systems, with a focus on models of the vasculature. The cardiovascular system transports all necessary substances, including drugs, throughout the body while in charge of thermal regulation and communication between other organ systems. In addition, we discuss the benefits, limitations, and challenges in the widespread use of new biomedical models. Coupled with patient-derived induced pluripotent stem cells, organ-on-a-chip technologies are the future of drug discovery, development, and personalized medicine.

On the Recent Changes to Animal Protection Measures in United States Food and Drug Administration Policy

ASSAY and Drug Development TechnologiesVol. 21, No. 1 EditorialOn the Recent Changes to Animal Protection Measures in United States Food and Drug Administration PolicyBruce J. MelanconBruce J. MelanconAddress correspondence to: Bruce J. Melancon, PhD, Department of Pharmacology, Vanderbilt School of Medicine, Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA E-mail Address: bruce.melancon@vanderbilt.eduEditor-in-ChiefDepartment of Pharmacology, Vanderbilt School of Medicine, Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA.Search for more papers by this authorPublished Online:17 Jan 2023https://doi.org/10.1089/adt.2023.29103.bjmAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"On the Recent Changes to Animal Protection Measures in United States Food and Drug Administration Policy." ASSAY and Drug Development Technologies, 21(1), pp. 1–2FiguresReferencesRelatedDetails Volume 21Issue 1Jan 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Bruce J. Melancon.On the Recent Changes to Animal Protection Measures in United States Food and Drug Administration Policy.ASSAY and Drug Development Technologies.Jan 2023.1-2.http://doi.org/10.1089/adt.2023.29103.bjmPublished in Volume: 21 Issue 1: January 17, 2023PDF download