Tag archive for therapeutic

New Research Finds Novel Uses for Old Drugs

A recent article in C&EN reports that scientists at the University of North Carolina at Chapel Hill School of Medicine and the University of California, San Francisco have developed and experimentally tested a technique to predict new target diseases for existing drugs. The team, led by Bryan L. Roth and Brian K. Shoichet, developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring ligands of disease targets within cells. In their study, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat since many drugs have been found to bind to multiple targets. Sometimes these interactions lead to new uses for well established drugs. At other times, they may cause harmful side effects. Either way, knowing about these interactions allows for better use of drugs.

In the new method, drug receptors are not defined by structure or sequence but by the ligands that bind to them. This approach differs from structure-based approaches which usually use a receptor’s crystal structure as a starting point.

“This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, M.D., Ph.D., professor of pharmacology and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” internetchemistry.com

By using a modified version of an already established algorithm used to search gene-sequence databases, compounds were screened against a database of targets, asking how much the compounds looked like the ligands. The team compared 3,665 approved or investigational drugs with hundreds of targets which were defined by their ligands. The researchers predicted thousands of unanticipated interactions and experimentally tested 30 of them. Of these 30, they confirmed 23 of the interactions.

In one case, the team found  that Rescriptor, which inhibits the enzyme HIV reverse transcriptase, also inhibited the histamine H4 receptor. The scientists have linked Rescriptor binding to histamine H4 at physiologically relevant concentrations to some of the painful side effects that the drug has. In another example, the antidepressant Prozac, whose primary target is the serotonin transporter, bound the beta-1 adrenerfic receptor, a G-protein-coupled receptor (GPCR) that usually binds such compounds as epinephrine and norepinephrine.

Roth states that the power of their approach is that it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug. Consequently, this new method will be an important step forward for chemists to design drugs that act on multiple targets.

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A Natural Lock on Tumor Growth

At the University of California, researchers have been studying RNA interface(RNAi), a naturally occurring system that turns genes on and off, and the proteins drosha and dicer. The research has focused on spacial and temporal regulations of RNAi. Researchers hope that a better understanding of these regulations will help to lead to improved medical applications of controlling the RNAi system. This emerging research is going to be essential in future medical endeavors especially in biomedical applications such as gene therapy.

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Research on drosha and dicer proteins is already being applied to the medical field. According to a study in the New England Journal of Medicine, women who had ovarian tumors with high levels of the proteins Dicer and Drosha survived for an average of 11 years or more, while women who had lower levels survived only a median of around 3 years. Researchers hope that a better understanding of Dicer and Drosha might someday help guide treatment or lead to new types of therapy. These two proteins are essential in RNA interference. In the study, Anil K. Sood, M.D., University of Texas M.D. Anderson Cancer Center, in Houston, and his colleagues looked for Dicer and Drosha in the tissue from 111 women with advanced epithelial ovarian cancer. They found that 60 percent of the cancer tissues had low levels of Dicer, 51 percent had low levels of Drosha, and 39 percent had low levels of both. This study is the largest yet to link RNA interface with any cancer survival rates.

“In the past, people used to think that miRNA might actually promote tumor growth, but there is some emerging thought that some of the miRNAs might keep tumors from growing and actually function as a tumor suppressor,” says Sood, who is an associate professor of cancer biology.

Unfortunately this research does not have immediate application for women with ovarian cancer. However the finding may eventually help doctors to better determine if a patient needs more aggressive treatments.

This new research is causing many biotechnology companies to look at this lock-and-key mechanism as a potential way to fight other diseases. They are working to create new synthetic molecules called small interfering RNAs. These siRNAs are being tested as a way to treat eye disease and age-related macular degeneration.

J. Am. Chem. Soc., 2009. DOI: 10.1021/ja905596t

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New Gene Therapy Technique Provides a Breath of Fresh Air for Lung Donor Recipients

A group of researchers at the University Health Network of Toronto led by Dr. Shaf Keshavjee, developed a novel gene therapy technique that repaired donated lungs deemed too damaged to transplant. The group’s findings, “Functional Repair of Human Donor Lungs by IL-10 Gene Therapy” were published in the October 28, 2009 edition of the journal Science Translational Medicine. Their simple and effective technique could significantly increase the number of available lungs for people desperately in need.

Lungs-close-up-lrgAs it stands, only about 15 percent of lungs donated are usable for transplant. Because doctors injure delicate airways as they try to keep donors alive, or the brain death of the donors causes further damage through massive inflammation of the lung tissue. Lungs that make it to transplantation are still vulnerable to inflammation during the first 72 hours after surgery. Overall, only about 40% of lung transplant recipients survive five years after receiving their new lungs.

The research conducted by the University Health Network’s team focused on saving donated lungs that would otherwise be discarded and, eventually, to improve patient outcomes after transplantation. The most important component of their study is the interleukin-10 gene, IL-10. Among IL-10’s many roles is inhibiting the immune response to infection or foreign materials, like transplanted organs. The research strategy consisted of two parts. The first preserved lungs at normal body temperature in a protective dome called the Toronto XVIVO Lung Perfusion System. The dome continuously pumps oxygen devoid of blood, proteins, and nutrients into the injured lungs to mimic normal body conditions. This made it possible for the injured cells to regenerate themselves. In the second part, researchers injected an adenovirus vector, a common cold virus, along with the IL-10 gene through the windpipe into the lungs. After testing the technique with lungs from pigs and then human donors, the team concluded that the gene therapy significantly improved the ability of the lungs to take in oxygen as well as expel carbon dioxide. The therapy improved blood flow throughout the lungs and lasted for up to 30 days. None of the tested lungs were transplanted into patients; however, future plans include starting clinical trials on humans and testing whether this therapy could protect against post-transplant inflammation.

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Who needs embryonic cells anyway?

An article released in Science last August (Induced Pluripotent Stem Cells Generated from Patients with ALS can be Differentiated into Motor Neurons) prompted Time Magazine to name the discovery the No. 1 Medical Breakthrough of the Year. Collaborators at Harvard University and Columbia University based their research on a previous breakthrough that suggested the feasibility of reprogramming somatic cell nuclei into an undifferentiated state by a process called somatic cell nuclear transfer. While the Obama administration recently reversed the limits Bush had previously imposed on embryonic stem cell research, it is of no consequence to this team of scientists, who opened the door to stem cell research involving skin cells rather than human embryonic cells.

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The motivation for their ground-breaking work is the state of research on ALS, or Lou Gehrig’s disease. Once referred to as an orphan disease, ALS is finally getting the attention it deserves as an incurable and mysterious neurodegenerative disease. The cause of the disease is currently unknown, but a supply of human motor neurons carrying the genes responsible for the disease would be highly beneficial to research and eventual treatment. Unlike other disease research where the affected cells can be removed from patients and examined, obtaining a diseased model of a motor neuron or glial (support) cell is unheard of making investigation of degeneration of the cells very difficult.

The team of scientists used skin cells extracted from two elderly ALS patients and transduced the fibroblasts with four genes previously determined to return cells to an undifferentiated state. This is possible because embryogenesis is not dictated by genetic events; it is actually reversible! Imagine that! From the skin cells, the scientists were able to produce iPS colonies (induced pluripotent stem cells), which are very similar to ES cells in morphology and expression. One success after another, they pressed on in hopes of differentiating these cells into motor neurons and glial cells.

I had the opportunity to work with the team of collaborators at Columbia University two summers ago when they were developing a concrete procedure for the differentiation of mouse and human ES cells into motor neurons. It was with this method that the scientists ultimately created motor neurons from simple skin biopsies. While this research was done on patients who expressed the SOD1 allele (or the gene pinpointed in familial ALS), 90% of ALS cases are sporadic, meaning there is no genetic history of the disease. The research is far from null though; it actually provides great insight into the sporadic form of the disease, which is believed to be caused by a combination of genetic and environmental factors. Once a more stable method of reproduction is determined, this research should have a great impact on research and clinical trials for patients with ALS and other neurodegenerative diseases.

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MotW13 – A Potential Metal-Free Cancer Drug

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Metal-DNA adducts are popular molecules for cancer treatment.  However, the metal-based drugs have been associated with unwanted side effects such as nausea, nephrotoxicity (toxicity to kidney cells), and myelosuppression (suppression of bone marrow activity).  Researchers have therefore been geared toward synthesizing metal-free cancer drugs.  A research team at the Indian Institute of Technology in Bombay  has created a new bis(phosphite) ligand) and corresponding complexes of selenium and gold with thioether functionalities (D. Suresh, Maravanji S. Balakrishna, Krishnan Rathinasamy, Dulal Panda and Joel T. Mague Dalton Trans., 2008, 2285 – 2292).

All three compounds were examined for cytotoxic activity in a HeLa (human cervix epitheloid carcinoma) cell line.  While the bis(phosphite) ligand and bis(sulfide) derivative of the ligand significantly inhibited growth of the HeLa cells, the selenium and gold complexes did not.  By testing both the bis(phosphite) ligand and bis(sulfide) derivative in the HeLa line with annexin V and a propidium iodide apoptosis detection kit, the researchers discovered that both compounds caused cell death by apoptosis, using specialized mechanisms within the cell to shed membrane-bound particles.  The creation of a cancer drug that could potentially reduce or eliminate the side effects of metal-based drugs could help make treatment more bearable for patients as well as possibly attack resistant cells more effectively.

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MotW12 – potential prodrugs for Alzheimer’s disease

MotW12-b815404j-co340wThe molecule for this week comes from research out of the Medicinal Inorganic Chemistry Group at the University of British Columbia in Vancouver and concerns altering pyridinone N-substituents to optimize activity as potential prodrugs for Alzheimer’s disease (Lauren E. Scott, Brent D. G. Page, Brian O. Patrick and Chris Orvig. Dalton Trans., 2008, 6364 – 6367). The research focuses on using metal-binding pyridinone prodrugs for Alzheimer’s disease treatment because of their brain targeting abilities as well as their antioxidant characteristics. Pyridinones are already approved for therapeutic purposes in some areas of the world and, since hydroxypridinones are good at binding to metals, the N-substituent can be modified which in turn alters the structure without changing metal binding capabilities.

In previous research, it was found that molecules that contain a glucose moiety can easily target the brain. Based on this, the researchers aimed to attach a glucose moiety at the 3-hydroxyl oxygen.  This glucose moiety can then be enzymatically removed once the molecule reaches the target leaving the metal binding agent. The copper complexes 3-Hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp) were synthesized. Copper was used as it is one of the redox active metals involved in Alzheimer’s disease and because it has a higher affinity for amerliorate toxic beta-amyloid deposits, which are found in the brains of affected patients.  It was found that the Hppp and Hnbp significantly reduced the amount of amerliorate toxic beta-amyloid deposits and there was no significant difference between the Hppp copper complex and the Hnbp copper complex in efficiency.

I found this research both interesting and important as there is currently no cure for Alzheimer’s disease. It is also interesting to see how inorganic chemistry can be applied to solving problems in medical and biological settings . I am hopeful that in a few years we will see a similar drug or concept that will help cure Alzheimer’s disease.

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