The Medicinal Chemistry of Therapeutic Peptides: Recent Developments in Synthesis and Design Optimizations

2019 ◽  
Vol 26 (13) ◽  
pp. 2330-2355 ◽  
Author(s):  
Anutthaman Parthasarathy ◽  
Sasikala K. Anandamma ◽  
Karunakaran A. Kalesh
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
The Past ◽  
Recombinant Production ◽  
Tremendous Progress ◽  
Recent Developments ◽  
Therapeutic Peptides ◽  
Development Processes ◽  
Delivery Strategies

Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered ‘undruggable’.

scholarly journals Stability of Screening Compounds in Wet DMSO

2008 ◽  
Vol 13 (10) ◽  
pp. 999-1006 ◽  
Author(s):  
Caroline Engeloch ◽  
Ulrich Schopfer ◽  
Ingo Muckenschnabel ◽  
Francois Le Goff ◽  
Hervé Mees ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Medicinal Chemistry ◽  
Storage Conditions ◽  
Pragmatic Approach ◽  
Analytical Quality ◽  
The Past ◽  
Effect Of Water ◽  
The Impact

The impact of storage conditions on compound stability and compound solubility has been debated intensely over the past 5 years. At Novartis, the authors decided to opt for a storage concept that can be considered controversial because they are using a DMSO/water (90/10) mixture as standard solvent. To assess the effect of water in DMSO stocks on compound stability, the authors monitored the purity of a subset of 1404 compounds from ongoing medicinal chemistry projects over several months. The study demonstrated that 85% of the compounds were stable in wet DMSO over a 2-year period at 4 °C. This result validates the storage concept developed at Novartis as a pragmatic approach that takes advantage of the benefits of DMSO/water mixtures while mediating the disadvantages. In addition, the authors describe how purity data collected over the course of the chemical validation of high-throughput screening actives are used to improve the analytical quality of the Novartis screening deck. ( Journal of Biomolecular Screening 2008:999-1006)

scholarly journals Multidimensional Profiling of CSF1R Screening Hits and Inhibitors

2011 ◽  
Vol 16 (9) ◽  
pp. 1007-1017 ◽  
Author(s):  
Joost C. M. Uitdehaag ◽  
Cecile M. Sünnen ◽  
Antoon M. van Doornmalen ◽  
Nikki de Rouw ◽  
Arthur Oubrie ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Active Form ◽  
Dissociation Rate ◽  
The Past ◽  
Compound Libraries ◽  
Competitive Kinetics ◽  
Homogeneous Assay ◽  
High Throughput Assay ◽  
Stimulating Factor

Over the past years, improvements in high-throughput screening (HTS) technology and compound libraries have resulted in a dramatic increase in the amounts of good-quality screening hits, and there is a growing need for follow-on hit profiling assays with medium throughput to further triage hits. Here the authors present such assays for the colony-stimulating factor 1 receptor (CSF1R, Fms), including tests for cellular activity and a homogeneous assay to measure affinity for inactive CSF1R. They also present a high-throughput assay to measure target residence time, which is based on competitive binding kinetics. To better fit koff rates, they present a modified mathematical model for competitive kinetics. In all assays, they profiled eight reference inhibitors (imatinib, sorafenib, sunitinib, tandutinib, dasatinib, GW2580, Ki20227, and J&J’s pyrido[2,3-d]pyrimidin-5-one). Using the known biochemical selectivities of these inhibitors, which can be quantified using metrics such as the selectivity entropy, the authors have determined which assay readout best predicts hit selectivity. Their profiling shows surprisingly that imatinib has a preference for the active form of CSF1R and that Ki20227 has an unusually slow target dissociation rate. This confirms that follow-on hit profiling is essential to ensure that the best hits are selected for lead optimization.

scholarly journals Fluorescence Polarization and Anisotropy in High Throughput Screening: Perspectives and Primer

2000 ◽  
Vol 5 (5) ◽  
pp. 297-306 ◽  
Author(s):  
John C. Owicki
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Fluorescence Polarization ◽  
High Throughput Screening ◽  
The Past ◽  
Assay Performance ◽  
The Subject ◽  
Homogeneous Assays

Fluorescence polarization and anisotropy are two nearly equivalent techniques that have together, over the past 5 years, achieved wide use in high throughput screening in drug discovery. These are single-label methods that can be used to construct homogeneous assays that are fast, sensitive, and resistant to some significant interferences. Moreover, the assays are relatively inexpensive. This review surveys the peer-reviewed literature on the subject and explores some of the fundamental issues that bear on assay performance.

Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1

2020 ◽  
Vol 26 (1) ◽  
pp. 140-150
Author(s):  
Ann M. Decker ◽  
Kelly M. Mathews ◽  
Bruce E. Blough ◽  
Brian P. Gilmour
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Calcium Mobilization ◽  
Hit Rate ◽  
Wide Range ◽  
Trace Amine ◽  
The Central Nervous System ◽  
Calcium Mobilization Assay

The human trace amine-associated receptor 1 (hTAAR1) is a G protein-coupled receptor (GPCR) that is widely expressed in monoaminergic nuclei in the central nervous system and has therapeutic potential for multiple diseases, including drug addiction and schizophrenia. Thus, identification of novel hTAAR1 ligands is critical to advancing our knowledge of hTAAR1 function and to the development of therapeutics for a wide range of diseases. Herein we describe the development of a robust, 3-addition high-throughput screening (HTS) calcium mobilization assay using stable CHO-Gαq16-hTAAR1 cells, which functionally couple hTAAR1 to the promiscuous Gαq16 protein and thus allow signal transduction to occur through mobilization of internal calcium. Our previously established 96-well hTAAR1 assay was first miniaturized to the 384-well format and optimized to provide an assay with a Z′ factor of 0.84, which is indicative of a robust HTS assay. Using the 3-addition protocol, 22,000 compounds were screened and yielded a ~1% agonist hit rate and a ~0.2% antagonist hit rate. Of the antagonist hits, two confirmed hits are the most potent hTAAR1 antagonists identified to date (IC50 = 206 and 281 nM). While scientists have been studying hTAAR1 for years, the lack of suitable hTAAR1 antagonists has been a major roadblock for studying the basic pharmacology of hTAAR1. Thus, these new ligands will serve as valuable tools to study hTAAR1-mediated signaling mechanisms, therapeutic potential, and in vivo functions.

scholarly journals A Cell-Based High-Throughput Screening Assay for Posttranscriptional Utrophin Upregulation

2012 ◽  
Vol 18 (4) ◽  
pp. 400-406 ◽  
Author(s):  
Catherine Moorwood ◽  
Neha Soni ◽  
Gopal Patel ◽  
Steve D. Wilton ◽  
Tejvir S. Khurana
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Posttranscriptional Regulation ◽  
Therapeutic Potential ◽  
Dystrophin Gene ◽  
Screening Assay ◽  
Expression Screening ◽  
High Throughput Screening Assay ◽  
Promising Therapeutic Approach ◽  
Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease caused by mutations in the dystrophin gene. Utrophin is a homologue of dystrophin that can compensate for its absence when overexpressed in DMD animal models. Utrophin upregulation is therefore a promising therapeutic approach for DMD. Utrophin is regulated at both transcriptional and posttranscriptional levels. Transcriptional regulation has been studied extensively, and assays have been described for the identification of utrophin promoter-targeting molecules. However, despite the profound impact that posttranscriptional regulation has on utrophin expression, screening assays have not yet been described that could be used to discover pharmaceuticals targeting this key phase of regulation. We describe the development and validation of a muscle cell line–based assay in which a stably expressed luciferase coding sequence is flanked by the utrophin 5′- and 3′-untranslated regions (UTRs). The assay was validated using the posttranscriptional regulation of utrophin by miR-206. The assay has a Z′ of 0.7, indicating robust performance in high-throughput format. This assay can be used to study utrophin regulatory mechanisms or to screen chemical libraries for compounds that upregulate utrophin posttranscriptionally via its UTRs. Compounds identified via this assay, used alone or in a synergistic combination with utrophin promoter-targeting molecules, would be predicted to have therapeutic potential for DMD.

scholarly journals Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

2018 ◽  
Author(s):  
Sara E. Kearney ◽  
Gergely Zahoránszky-Kőhalmi ◽  
Kyle R. Brimacombe ◽  
Mark J. Henderson ◽  
Caitlin Lynch ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Structural Diversity ◽  
Biological Evaluation ◽  
Structural Class ◽  
Differential Behavior ◽  
Biological Potential ◽  
Approved Drugs

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (–)-2(<i>S</i>)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

High Throughput Screening of Waterbased Coating Formulations

2009 ◽  
Vol 1159 ◽  
Author(s):  
John Roper ◽  
Michael Johnson ◽  
Melinda Keefe ◽  
Jodi Mecca ◽  
Richard Cesaretti
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Waterborne Coatings ◽  
The Past ◽  
Research Areas ◽  
Complex Interactions ◽  
Evaluation Of Performance ◽  
Architectural Coatings ◽  
Speed To Market ◽  
Formulation Variables

AbstractSince 1998, Dow has been actively developing and applying high throughput research (HTR) methodologies to increase the speed to market and the probability of successful product introductions. Initially Dow implemented this approach in the area of homogeneous catalysis. Based upon the success in this area, high throughput methods have been expanded into other research areas such as waterborne coatings. Paint formulations offer an excellent opportunity to use the strengths of high throughput research to understand how complex interactions between many components affect final properties. High throughput tools enable the rapid and reproducible development of paints, preparation of coating on substrates, and evaluation of performance. Rapid formulation and testing allows the interactions between formulation variables to be investigated in much more depth and breadth than has been possible in the past. Finally, statistical anaylsis and data mining tools can be used to optimize a desired balance of properties within customer defined constraints. This paper presents an example of using Dow's HTR coatings workflow to improve properties for low VOC / low odor architectural coatings.

The Future of High-Throughput Screening

2008 ◽  
Vol 13 (6) ◽  
pp. 443-448 ◽  
Author(s):  
Lorenz M. Mayr ◽  
Peter Fuerst
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Biological Data ◽  
Steady Increase ◽  
Continuous Change ◽  
Lead Discovery ◽  
The Past ◽  
Basic And Applied Research ◽  
Set Up

High-throughput screening (HTS) is a well-established process in lead discovery for pharma and biotech companies and is now also being set up for basic and applied research in academia and some research hospitals. Since its first advent in the early to mid-1990s, the field of HTS has seen not only a continuous change in technology and processes but also an adaptation to various needs in lead discovery. HTS has now evolved into a quite mature discipline of modern drug discovery. Whereas in previous years, much emphasis has been put toward a steady increase in capacity (“quantitative increase”) via various strategies in the fields of automation and miniaturization, the past years have seen a steady shift toward higher content and quality (“quality increase”) for these biological test systems. Today, many experts in the field see HTS at the crossroads with the need to decide either toward further increase in throughput or more focus toward relevance of biological data. In this article, the authors describe the development of HTS over the past decade and point out their own ideas for future directions of HTS in biomedical research. They predict that the trend toward further miniaturization will slow down with the implementation of 384-well, 1536-well, and 384 low-volume-well plates. The authors predict that, ultimately, each hit-finding strategy will be much more project related, tailor-made, and better integrated into the broader drug discovery efforts. ( Journal of Biomolecular Screening 2008:443-448)

From stereodynamics to high-throughput screening of catalysed reactions

2014 ◽  
Vol 50 (92) ◽  
pp. 14301-14309 ◽  
Author(s):  
Skrollan Stockinger ◽  
Julia Gmeiner ◽  
Kerstin Zawatzky ◽  
Johannes Troendlin ◽  
Oliver Trapp
Keyword(s):  
Chemical Analysis ◽  
High Throughput ◽  
High Throughput Screening ◽  
Recent Developments

In this review we summarised recent developments in high-throughput kinetic monitoring of reactions including the dynamics of interconverting stereoisomers and the simultaneous combination of (catalysed) reactions with chemical analysis in on-column reaction chromatographic devices.

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