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Huberfeld Alexandra 2021 OA the Application.Pdf (1.008Mb) The Applications of High Throughput Screening and its Value as a Drug Discovery Tool in the Pharmaceutical Industry and Academia Presented to the S. Daniel Abraham Honors Program in Partial Fulfillment of the Requirements for Completion of the Program Stern College for Women Yeshiva University April 27, 2021 Alexandra Huberfeld Mentor: Dr. Alyssa Schuck Huberfeld 1 Table of Contents: Abstract 2 Introduction 3 Classical Pharmacology 3 Reverse Pharmacology 4 High Throughput Screening 5 History of High Throughput Screening 6 Process of High Throughput Screening 7 Target Identification and Validation 7 Assay Development 8 SLC13A5 Deficiency and NaCT 10 Introduction 10 Assay Development for High Throughput Screening for NaCT Activator 11 Creating a Construct for Expressing NaCT in E. coli 13 Creating a Positive Control Using CitS 16 Expressing NaCT on pET Vectors With the Addition of IPTG 18 Conducting a Screen 22 Recent Developments 23 Arguments Against High Throughput Screening 24 Arguments In Favor of High Throughput Screening 25 High Throughput Screening in Academia 26 Conclusions 28 Acknowledgments 28 Works Cited 29 Huberfeld 2 Abstract High throughput screening is a method of drug development that has become increasingly popular in the past three decades. Since its populariZation in the 1990s, it has been criticiZed by proponents of typical drug development strategies as costly and ineffective. This paper outlines the technique of high throughput screening, its history, and present uses. Using the design of a screen to identify small molecule activators for a sodium-citrate transporter in order to treat SLC13A5 Deficiency, the process of high throughput screening is outlined. The paper argues that while investing in the process is valuable for large pharmaceutical companies, it is not justifiable for academic researchers. Huberfeld 3 Introduction Classical Pharmacology Historically, drugs have been developed in several different ways. The first is through the discovery of natural products and adaptation towards drug use. An effect of a drug is first observed in a biological system, and then an effort is made to understand why the drug has that effect. This is known as classical pharmacology. The discovery of the antibiotic penicillin by Alexander Fleming in 1928 is an example of a drug developed through a product created naturally. Often, as with penicillins, these types of discoveries are serendipitous, first relying on luck to uncover a natural product that has the desired consequence. Once the organic compound is identified, then it can be fine-tuned and made into a drug for wide production and made safe to be consumed. Through nearly a century of research and development, penicillins are now known as an entire class of drugs, subdivided into five groups, each with a different range of targets and effectiveness. (ACS, n.d.) For example, Penicillin G was the original antibiotic discovered by Fleming, but another compound, Penicillin V was isolated from the same strain of fungus and was found to be more acid-resistant, thus more compatible for oral consumption. Drugs developed from natural compounds are the results of lengthy trial and error and often take years, even decades, to reach the market. (Medline, n.d.) Another example of a drug class originally derived from nature is that of opiates. Originally isolated from poppy flowers, opium was used for centuries for pain relief and recreational use. However, as our understanding of opium increased, different chemicals were Huberfeld 4 isolated and adapted. Morphine, codeine, and heroine are all different versions of opium that were developed before the 18th century. Then Methadone, OxyContin, and Percocet were synthesiZed. Each iteration attempted to prevent the disastrous effect of addiction and increase the potency. (Foundation for a Drug Free World, n.d.) The history of opioids reflects a similar pattern of discovery to penicillin– a fortuitous natural discovery followed by a lengthy development period. Reverse Pharmacology The classical pharmaceutical approach described previously is not the only path to creating a successful drug. Another approach is called reverse pharmacology, in which the desired target is known, and chemicals are either synthesiZed or discovered to bind to the target. This target is usually some sort of protein involved in the desired pathway; a receptor or enzyme could be the object of this search. If the target is well known, researchers can engage in “rational design” in which a small molecule is created to bind to a target. By knowing the three- dimensional shape of a protein target, small molecules can be designed to specifically interact with it. This interaction can cause it to be activated, inactivated, or may have no effect whatsoever. (Mavromoustakos T. et al, 2011) However, if a target is not well-mapped, less exact methods need to be utiliZed. This involves exposing a target to a wide array of potential ligands, with the objective that some will successfully bind. This array of molecules includes synthetic molecules, but also features natural molecules, like ones used in classical pharmacology. Molecules that have been found to Huberfeld 5 successfully bind to the target are subject to further screening to determine if any of the ligands have the desired physiological effect, often using cellular and then animal models. If successful, the drug can be evaluated in a clinical trial, and then expanded for public use. This process involves much trial and error, often taking years from the time a hit is identified until it is available for the market. (Arulsamy et al., 2016) High Throughput Screening Reverse pharmacology has become more popular in recent decades, as the time- consuming process of classical pharmacology can fail to yield viable drugs even after decades of trial. In particular, screening technologies have become standard industry tools because it is more straightforward pathway to drug development, and the automation allows for hundreds of thousands of compounds to be screened in a short amount of time. The process seemingly promises results as long as enough chemicals are tested. This has led many pharmaceutical companies and universities to invest in screening as a drug discovery method and to amass enormous chemical libraries to be used in screens. Initially, the siZe of chemical libraries was between 10,000 to 100,000 compounds, however, in the early 2000s, some libraries reached 500,000 compounds (Maccaron et al., 2011). High throughput screening is a technique used in reverse pharmacology drug development in which automated equipment is used “to rapidly test thousands to millions of samples for biological activity at the model organism, cellular pathway, or molecular level.” (Attene-Ramos et al., 2014). What makes a regular screen into a “high throughput” one is hard to Huberfeld 6 define, but “is often defined by the rate, quantity, or automation level of the testing.” (Janzen, 2014) High throughput screening is a more advanced method of screening, which relies on the use of automatic equipment, instead of being performed by an individual or team of researchers. History of High Throughput Screening High throughput screening was developed by large pharmaceutical companies like PfiZer in the mid-late 1980s. In the course of developing a screening system of antibiotics against actinomycetes, bacteria in soil, the researchers at PfiZer wanted to increase the rate at which antibiotics could be tested for effectiveness. The lab was able to screen 10,000 samples per week in 1990, up from 800 per week in 1984. This was accomplished by the implementation of several different new technologies, including multi-well plates, up to 96-well plates, and multi-well pipettes. This increased the yield and rate of the screen, and this process was quickly expanded to other targets (Pareira and Williams, 2007). Other companies assembled their own chemical libraries and began to implement this technology as well through the 1990s when high throughput screening became popular. As the technology became more widely available, its evolution and optimiZation progressed. Plates became miniaturiZed, while the number of wells increased, allowing for an even greater number of samples to be tested. Current screens can even be conducted with 1,536, 3456, well plates (Janzen, 2014 and Pareira; Williams, 2007; Wleklinski et al., 2018). This was accomplished through the automation of the screen; by allowing robots to conduct and monitor the screens, the rate of the screen is no longer limited by human ability. Huberfeld 7 Process of High Throughput Screening Target Identification and Validation The first step in developing a drug through high throughput screening is identifying the target of the screen, meaning, the protein or cellular pathway whose behavior the researcher wishes to modify. This can often be based on decades worth of data into a particular protein’s role in the cell, and the structure of the protein could have possibly been identified. However, as was pointed out by William P. Janzen, the former Director of Assay Development and Compound Profiling at University of North Carolina, “in reality, the more you know about a target, the less likely you are to undertake a screen, making it almost a tool of desperation in de novo discovery.” (Janzen, 2014) Since high throughput screening is a method that does not require a complete understanding of the target, it is useful for proteins or targets that are not well understood. High throughput screening technology is more interested in finding a drug that modifies the target than understanding exactly how it accomplishes the change. One useful tool for initially identifying a target for a potential drug is RNA interference. Double-stranded RNA that codes for the candidate protein target is introduced into cells and triggers cellular mechanisms that result in the degradation of cellular mRNA coding for the target. This prevents the mRNA from being translated, and the effect on the cell can be assessed. In this way, a particular gene’s role in the cell can be elucidated.
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