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Yale J Biol Med. 2017 March; 90(1): 1–3.
Published online 2017 March 29.
PMCID: PMC5369027
Focus: Drug Development

Drug Development

In the March 2017 issue of the Yale Journal of Biology and Medicine (YJBM), we focus on the topic of Drug Development – the process of identifying and validating a small molecule or biologic with the potential to lessen human disease, and subsequently introducing it into the market for clinical use.

In the first stage of drug development, target identification and validation, researchers try to identify compounds that affect a biological pathway associated with a particular disease. These compounds can be identified from nature, from high-throughput screens of large compound libraries, or synthesized as analogs of other compounds that are known to be effective against a particular disease. After identifying potential lead compounds and studying their mechanism of action against the biological process of interest, initial safety tests are conducted in the laboratory. In these tests, researchers study a compound’s pharmacokinetics, or how the potential drug is processed in the body after administration to an organism, by examining its absorption, distribution, metabolism, and excretion. The effects of the drug on the organism’s physiology, or the pharmacodynamics, are also studied at this stage. Other considerations include the compound’s toxicity profile, potential side effects and interactions of the lead compound with other medications, and the route of administration.

The second stage consists of preclinical research conducted via in vitro and in vivo assays, including cellular as well as animal models, to determine if the agent is safe and suitable to test in humans. At this point, an IND (Investigational New Drug) application delineating the available animal study and toxicity data, clinical protocols, and manufacturing information, must be submitted to the FDA prior to progressing to the next stage. The third stage is comprised of clinical trials. These studies include Phase I clinical trials, in which the objective is to determine the safety and ideal dosage of a drug in a small number of healthy volunteers; Phase II trials, where the efficacy and side effects of the agent are further studied in a population of patients with the disease; and Phase III and IV trials, to further characterize efficacy and adverse reactions.

If drug development has been successful thus far, the process moves onto a fourth stage, in which a company files a New Drug Application (NDA) with the Food and Drug Administration (FDA). All the data obtained in the study of the agent is included with this application and, based on the information submitted, a multi-disciplinary team decides whether or not to approve the drug. At this stage, the FDA often requests additional studies to address questions raised by the NDA. If the drug is approved, the FDA works closely with the company submitting the NDA to develop appropriate prescribing information in a process known as “labeling.” After a drug is approved and in use, the FDA continues to monitor the safety and side-effects of the drug.

As is clear from the preceding paragraphs, the process of developing a drug and bringing it to the market is inherently complex, and it requires a multi-disciplinary team working together over many years to introduce a new agent for clinical use. In addition to basic science researchers, clinicians, and pharmaceutical companies, the drug development process also requires essential input from statisticians, pharmacists, and even ethicists. In this issue of YJBM, we offer articles highlighting the multi-faceted nature of drug development, ranging from an original research article by Thakral and Tae describing the synthesis and use of a new compound to inhibit translation in Bacillus subtilis, to a perspective piece submitted by Daniel Shaw detailing how an “Open Science” approach could prove efficacious to the process of developing new medications. In addition, we also present the following articles included in the issue:

Liu et al. describe in an original research report their investigations of how exercise intensity affects pain related behaviors and c-Fos expression in an animal model system. The authors point out their work opens up many new questions related to molecular targets for the development of pain medications.

Gusman and Shoemake present original research toward the in silico design of novel sphingosine-1-phosphate receptor modulators for the treatment of multiple sclerosis (MS), with the goal of producing candidates with reduced side effect profiles compared to known modulators. Basing their design on the scaffolds of Fingolimod and Amiselimod, they identify several structures suitable for further optimization.

Meier and Grose present their original research findings on the effects of trehalose on the viral spread of varicella zoster virus (VZV) and cytomegalovirus (CMV). The authors find that, regardless of viral type, cells either treated with trehalose prior to viral inoculation or simultaneously treated with trehalose and cell-free virus both show decreased viral spread. On the other hand, they find that cells inoculated with infected cells of either virus type prior to being treated with trehalose do not show a decrease in viral spread. These results contrast with previous findings that trehalose positively impacts VZV viral spread and negatively impacts CMV viral spread through increasing autophagy.

DiChiara et al. offer a thorough review of the role of toxic amyloid beta oligomers (AβOs) in Alzheimer’s disease, and present original data bolstering the hypothesis that AβOs attach to specific membrane protein complexes containing Na+/K+ ATPase-α3, leading to neuronal pathology through inhibition of ATPase activity and downstream intracellular calcium excess.

Shin and Bayarsaihan offer an in-depth review of the inhibition of the bromodomain and extra-terminal (BET) family of epigenetic readers. They describe the molecular mechanisms responsible for inhibition of the BET family, list potential diseases that could be treated by suppressing BET proteins, and discuss the role of BET protein inhibition in treating bone and gingival diseases.

Prabhakar et al. present a review describing strategies to modulate epigenetic mechanisms by targeting long noncoding RNAs (lncRNAs). The review begins by discussing various aspects of epigenetic regulation of gene expression. The latter part of the review addresses the role of lncRNAs in disease and their mechanisms, and describes potential methods to target lncRNAs in vivo.

Krishnan et al. describe in detail the role of hemi-channels in health and disease and draw attention to the relative lack of screening assays to assess how potential therapeutic agents affect hemi-channel function. The authors go on to outline how they have recently developed an efficacious assay in bacteria, which they envision to be easily adapted by other research groups.

Olson et al. outline in their review the current state of chronic pain management research, including efforts to develop opioid-like drugs with reduced side effect profiles. Several novel strategies they discuss include designing functionally selective ligands to activate only certain signaling cascades; designing multi-functional molecules that will activate the opioid receptor while blocking negative feedback receptor systems responsible for side effects; targeting heterodimers of the opioid and other receptor systems; and making endogenous opioid peptides druggable.

Lu et al. present a well-written review in which they discuss novel agents to be used for treating primary open-angle glaucoma. After a concise discussion of the pathophysiology of open-angle glaucoma, the authors discuss the use of rho kinase inhibitors, adenosine receptor agonists, and modified prostaglandin analogs in clinical trials.

Wang and Huang provide a review of drug development against metastatic cancers. Following a brief review of the many difficulties of developing therapeutics against neoplasms, the authors point out that metastatic cancer cells have unique features that can potentially be targeted with drugs, and they end their piece describing a lead compound they recently identified that has shown potential as an inhibitor of metastasis.

Brown et al. contribute an intriguing review in which they detail the many ways in which investigating new drugs would benefit by having a pharmacist as a member of the research team. They argue that including a pharmacist is vital to ensuring new drugs are safe and efficacious, and they also articulate the many areas of the clinical trial process that would benefit as a result of such an inclusion.

In their perspective piece, Lobanovska and Pilla provide a historical review of the development of penicillin, and draw attention to the problems posed by the rise of antimicrobial resistance (AMR). They recommend the international implementation of strict regulation of antibiotic use, the development of alternative therapies such as vaccines and antimicrobial peptides, and the development of techniques to diagnose bacterial infection in order to combat the rise of AMR.

Finally, we present an interview with Dr. Chirag R. Parikh, Professor of Medicine and Director of the Program of Applied Translational Research (PATR) at the Yale School of Medicine. Dr. Parikh conducts patient-oriented research aimed at developing better biomarkers for kidney diseases to facilitate therapeutic and diagnostic decisions. Dr. Parikh also spoke about how he became interested in translational research, advice he has for those interested in careers in translational research and drug development, and what he sees as the future of translational research.

As the range of articles in this issue of YJBM suggests, the topic of Drug Development spans a multitude of disciplines. Indeed, we could devote a few more issues to Drug Development and still have many areas within the field that have not received full attention. Thus, it has been a particular focus to include a diverse collection of manuscripts to draw attention to the many aspects of what is involved in successfully developing a therapeutic. We hope this issue helps to illustrate the numerous challenges associated with the process, in addition to highlighting the many exciting opportunities in the future for lessening human disease.

Abbreviations

IND
Investigational New Drug
NDA
New Drug Application
FDA
Food and Drug Administration
MS
multiple sclerosis
VZV
varicella zoster virus
CMV
cytomegalovirus
AβOs
amyloid beta oligomers
BET
bromodomain and extra-terminal
lncRNAs
long noncoding RNAs
AMR
antimicrobial resistance
PATR
Program of Applied Translational Research

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine