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White Paper - Biopharmaceutics Modelling as a Fundamental Tool to Support Accelerated Access
No full textUsing a combination of advanced bio-relevant in-vitro systems and in-silico Physiologically Based Pharmacokinetic (PBPK) models, in combination with agile and information-rich clinical study designs will enable rapid development and change management of drug products with optimal performance
Clinically established biodegradable long acting injectables: An industry perspective
No full textLong acting injectable formulations have been developed to sustain the action of drugs in the body over desired periods of time. These delivery platforms have been utilized for both systemic and local drug delivery applications. This review gives an overview of long acting injectable systems that are currently in clinical use. These products are categorised in three different groups: biodegradable polymeric systems, including microparticles and implants; micro and nanocrystal suspensions and oil-based formulations. Furthermore, the applications of these drug delivery platforms for the management of various chronic diseases are summarized. Finally, this review addresses industrial challenges regarding the development of long acting injectable formulations
Fragment-to-Lead Medicinal Chemistry Publications in 2019
No full textFragment-based drug discovery (FBDD) has grown and matured to a point where it is valuable to keep track of its extent and details of application. This Perspective summarizes successful fragment-to-lead stories published in 2019. It is the fifth in a series that started with literature published in 2015. The analysis of screening methods, optimization strategies, and molecular properties of hits and leads are presented in the hope of informing best practices for FBDD. Moreover, FBDD is constantly evolving, and the latest technologies and emerging trends are summarized. These include covalent FBDD, FBDD for the stabilization of proteins or protein-protein interactions, FBDD for enzyme activators, new screening technologies, and advances in library design and chemical synthesis
Disappearing disorder
No full textSingle crystal X-ray diffraction is the method of choice to resolve difficult solid-state problems. This is exemplified by analysis of three disordered structures that cease to be disordered depending on the circumstances. Interesting research questions of relevance for the pharmaceutical industry, including possible issues of intellectual property, emerge from disappearing disorder phenomena. Its relationship to polymorphism is discussed, and the term ‘archetype structure’ that includes both polymorphs and disorder components is recommended for use. X-ray structural studies reported here benefit from refinement with aspherical scattering factors that improve accuracy and precision of the results, thereby providing the confidence required in interpreting comparably small residual electron density features. Full understanding of the mechanism of how disorder can come into existence and disappear with temperature or time (pressure being another factor not exploited here) requires computing the relative energy differences of archetype structures by ONIOM cluster or solid-state computations
Biochemical characterization of respiratory syncytial virus RNA dependent RNA polymerase complex
No full textRNA dependent RNA polymerases (RdRP) from non-segmented negative strand (NNS) RNA viruses perform both mRNA transcription and genome replication and these activities are regulated by their interactions with RNA and other accessory proteins within the ribonucleoprotein (RNP) complex. Detailed biochemical characterization of these enzymatic activities and their regulation is essential for understanding the life cycles of many pathogenic RNA viruses and for antiviral drug discovery. We developed biochemical and biophysical kinetic methods to study the RNA synthesis and RNA binding activities of respiratory syncytial virus (RSV) L/P RdRP. We determined that the intact L protein is essential for RdRP activity and in truncated L protein constructs RdRP activity is abrogated due to their deficiency in RNA template binding. These results are in agreement with the observation of a RNA template-binding tunnel at the interface of RdRP and capping domains in RSV and vesicular stomatitis virus (VSV) L protein cryo-EM structures. We also describe a non-radiometric assay for measuring RNA polymerization activity of RSV RdRP that is amenable to compound screening and profiling
Pediatric pharmacokinetics and dose predictions: a report of a satellite meeting to the 10th Juvenile Toxicity Symposium
No full textOn the 24th of April 2019 a symposium on Pediatric pharmacokinetics and dose predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. The aim of this meeting was to bring together scientists from academia, industry and clinical research organizations to update each other on the current knowledge on pediatric drug development. The increased knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically based pharmacokinetic (PBPK) models has allowed a more integrated understanding of age-related differences in PK, for which examples were given during the meeting. PBPK may be considered the gold-standard for pediatric PK prediction, but still it is important to know that simpler methods like allometry, allometry combined with maturation function, functions based on the elimination pathway or linear models also perform well depending on the age range or the mechanisms involved. It is important to combine knowledge from different methods and information sources; e.g. techniques like microdosing can gain early read-out of age-related differences in exposure and in addition such results can be value to verify models. To further establish best practices for dose setting in pediatrics more in vitro and in vivo research is needed on such aspects as age related changes in the exposure response relationship and also the impact of disease on PK. New information coupled with the refining of model based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials
RNA-Catalyzed Cross-Chiral Polymerization of RNA
No full textBiology relies almost exclusively on homochiral building blocks to drive the processes
of life. Yet cross-chiral interactions can occur between macromolecules of the opposite
handedness, including a previously described polymerase ribozyme that catalyzes the template-directed synthesis of enantio-RNA. The present study sought to optimize and generalize this
activity, employing in vitro evolution to select cross-chiral polymerases that use either mono- or
trinucleotide substrates that are activated as the 5´-triphosphate. There was only modest
improvement of the former activity, but dramatic improvement of the latter, which enables the
trinucleotide polymerase to react 10^2–10^3-fold faster than its ancestor and to accept substrates
with all possible sequence combinations. The evolved ribozyme can assemble long RNAs from a
mixture of trinucleotide building blocks, including a two-fragment form of the ancestral
polymerase ribozyme. Further improvement of this activity could enable the generalized cross-chiral
replication of RNA, which would establish a new paradigm for the chemical basis of
Darwinian evolution
Advancements in assay technologies and strategies to enable drug discovery
No full textABSTRACT: Assays drive drug discovery from the exploratory phases to the clinical testing of drug candidates. As such, numerous assay technologies and methodologies have arisen to support drug discovery efforts. Robust identification and characterization of tractable chemical matter requires biochemical, biophysical, and cellular approaches and often bene-fits from high-throughput methods. To increase throughput, efforts have been made to provide assays in miniaturized volumes which can be arrayed in microtiter plates to support the testing of as many as 100,000 samples/day. Alongside these efforts has been the growth of microtiter plate-free formats with encoded libraries that can support the screening billions of compounds, a hunt for new drug modalities, as well as the emphasis on more disease relevant formats using complex cell models of disease states. This review will focus on recent developments in high-throughput assay technolo-gies applied to identify starting points for drug discovery. We also provide recommendations on strategies for implement-ing various assay types to select high quality leads for drug development