Aging biology and novel targets for drug discovery

Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become "blockbusters." To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process.     

Functional genomics and the discovery of new drug targets

Functional genomics can be defined as the search for the physiological role of a gene for which only its primary sequence is known. One example of a successful functional genomics adventure is the search for the natural ligands of orphan G protein-coupled receptors (GPCRs). GPCRs are proteins containing 7 hydrophobic domains that are the recognition sites of neurotransmitters and neuropeptides. Although many of these have been shown to interact with known natural ligands, several bind ligands that have not been thus far isolated. These are the so-called "orphan" GPCRs. As an example of functional genomics, an "orphan receptor strategy" has been developed to identify the natural ligands of orphan GPCRs. We describe that the application of this strategy has already led to the identification of 4 new neuropeptides and report on what has been learned about these neuropeptides. We finally discuss the importance of the application of the orphan receptor strategy to the development of novel drugs.     

The discovery of aspirin's antithrombotic effects

Aspirin has long been established as a useful analgesic and antipyretic. Even in ancient times, salicylate-containing plants such as the willow were commonly used to relieve pain and fever. In the 20th century, scientists discovered many details of aspirin's anti-inflammatory and analgesic properties, including its molecular mechanism of action. In addition, the latter half of the century brought reports that daily, low doses of aspirin could prevent myocardial infarction and stroke. This finding was first reported by Lawrence Craven, a suburban general practitioner in Glendale, California. Unfortunately, Craven's work went largely unnoticed, and decades passed before his observations were verified by clinical trial. We present Craven's story, which demonstrates the value of a single physician's commitment to lifelong learning. In addition, we summarize the work of the physicians and scientists who discovered the molecular mechanisms by which aspirin exerts its antiplatelet effects. Collectively, these discoveries exemplify the complementary roles of basic science and clinical observation in advancing medicine.     

Informatics resources for tuberculosis--towards drug discovery

Integration of biological data on gene sequence, genome annotation, gene expression, metabolic pathways, protein structure, drug target prioritization and selection, has resulted in several online bioinformatics databases and tools for Mycobacterium tuberculosis. Alongside there has been a growth in the list of cheminformatics databases for small molecules and tools to facilitate drug discovery. In spite of these efforts there is a noticeable lag in the drug discovery process which is an urgent need in the case of emerging and re-emerging infectious diseases. For example, more than 25 online databases are available freely for tuberculosis and yet these resources have not been exploited optimally. Informatics-centered drug discovery based on the integration and analysis of both bioinformatics and cheminformatics data could fill in the gap and help to accelerate the process of drug discovery. This article aims to review the current standing of developments in tuberculosis-bioinformatics and highlight areas where integration of existing resources could lead to acceleration of drug discovery against tuberculosis. Such an approach could be adapted for other diseases as well.     

Small animals models for drug discovery

There has been an explosion of studies of animal models of asthma in the past 20 years. The elucidation of fundamental immunological mechanisms underlying the development of allergy and the complex cytokine and chemokines networks underlying the responses have been substantially unraveled. Translation of findings to human asthma have been slow and hindered by the varied phenotypes that human asthma represents. New areas for expansion of modeling include virally mediated airway inflammation, oxidant stress, and the interactions of stimuli triggering innate immune and adaptive immune responses.     

Novel therapeutic targets for chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare, age-related myeloid neoplasm with overlapping features of myelodysplastic syndromes/myeloproliferative neoplasms. Although gene mutations involving TET2, ASXL1 and SRSF2 are common, there are no specific molecular alterations that define the disease. Allogeneic stem cell transplant is the only curative option, with most patients not qualifying, due to advanced age at diagnosis and comorbidities. The only approved treatment options are hypomethylating agents; drugs that fail to alter the disease course or affect mutant allele burdens. Clinically CMML can be sub-classified into proliferative (pCMML) and dysplastic (dCMML) subtypes, with pCMML being associated with signaling mutations, myeloproliferative features, and a shorter overall survival. Given the paucity of effective treatment strategies there is a need for rationally informed and biomarker driven studies. This report will discuss current and prospective therapies for CMML and discuss the role for personalized therapeutics.     

New drug targets for alcoholic liver disease

Alcoholic liver disease (ALD) represents a spectrum of disorders, ranging from simple steatosis to severe alcoholic hepatitis and cirrhosis. The severe form of ALD comprises multiple problems in the liver, including inflammation, hepatocellular damage, fibrosis, and impaired liver regeneration, and likely requires combinational therapies. In this review, we discuss recently identified therapeutic targets that inhibit inflammation, ameliorate hepatocyte death, and promote liver repair in ALD, with a focus on our recent studies on the immunosuppressive drug prednisolone and the hepatoprotective cytokine interleukin-22. Clinical trials examining prednisolone plus interleukin-22 therapy for severe alcoholic hepatitis are currently under consideration.     

New targets for drug development in asthma

Asthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15-20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and beta-adrenergic agonists; however, 5-10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies-such as the development of fast-onset, once-a-day combination drugs with better safety profiles-will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality.     

Novel targets for the control of secretory diarrhoea

Secretory diarrhoea continues to be a major clinical problem worldwide. It is now recognised that the enteric nervous system plays an important role in the pathogenesis of enterotoxin mediated intestinal secretion, which has resulted in the identification of novel therapeutic targets for the treatment of acute watery diarrhoea.     

Bioinformatics and rational drug design: tools for discovery and better understanding of biological targets and mode of action of drugs

BACKGROUND: With the advent of modern high throughput technologies in both genomics and biological screening, and at the same time the enormous advances in computer technology, it is now feasible to use these tools in rational approaches in the search for new medicines. The role of bioinformatics in the search for new medicines is discussed. METHODS: Discussion of the author's own work on bioinformatics in drug research in future perspective. RESULTS: The emerging discipline of Bioinformatics plays a central role in the concert of technologies of the 'biological revolution' because it allows for handling of the enormous data load that comes with sequencing efforts and subsequent analyses of whole genomes, with mRNA profiling techniques and, last but not least, at a later stage of drug discovery the up-to-date application of rational drug design techniques to 3D structures of target proteins. This article covers and explains parts of the steps used in modern pharmaceutical research by means of a small number of examples. CONCLUSION: Bioinformatics is likely to play a pivotal role in the rational approaches for the search of new medicines.     

Tachykinin receptors as drug targets for motility disorders

The tachykinins and their receptors are strategically distributed within the gut wall, spinal cord, and central nervous system to be potential targets of therapeutic agents for gastrointestinal motility disorders. However, the development of effective tachykinin receptor agonists or antagonists to treat these disorders has had very limited success so far. This is, in part, due to the complex and multilevel of regulation of gastrointestinal motility function and the challenges faced in targeting the specific type of gut contraction to normalize function in disease state.