Health and Medical News and Resources

General interest items edited by Janice Flahiff

[Repost] Database of Disease Genes Shows Potential Drug Therapies

From the 10 October 2013 article at newswise 

            [From the  article abstract – The Drug-Gene Interaction database (DGIdb) mines existing resources that generate hypotheses about how mutated genes might be targeted therapeutically or prioritized for drug development. It provides an interface for searching lists of genes against a compendium of drug-gene interactions and potentially ‘druggable’ genes. DGIdb can be accessed at http://dgidb.org/.]

Newswise — Researchers at Washington University School of Medicine in St. Louis have created a massive online database that matches thousands of genes linked to cancer and other diseases with drugs that target those genes. Some of the drugs are approved by the U.S. Food and Drug Administration, while others are in clinical trials or just entering the drug development pipeline.

The database was developed by identical twin brothers, Obi Griffith, PhD, and Malachi Griffith, PhD, whose interest in pairing drugs with genes is as much personal as it is scientific. Their mother died of breast cancer 17 years ago, just weeks before their high school graduation.

“We wanted to create a comprehensive database that is user-friendly, something along the lines of a Google search engine for disease genes,” explained Malachi Griffith, a research instructor in genetics. “As we move toward personalized medicine, there’s a lot of interest in knowing whether drugs can target mutated genes in particular patients or in certain diseases, like breast or lung cancer. But there hasn’t been an easy way to find that information.”

Details of the Drug Gene Interaction database are reported online Oct. 13 in Nature Methods. The database is weighted heavily toward cancer genes but also includes genes involved in Alzheimer’s disease, heart disease, diabetes and many other illnesses. The Griffiths created the database with a team of scientists at The Genome Institute at Washington University in St. Louis.

The database is easy to search and geared toward researchers and physician-scientists who want to know whether errors in disease genes – identified through genome sequencing or other methods – potentially could be targeted with existing drug therapies. Additional genes included in the database could be the focus of future drug development efforts because they belong to classes of genes that are thought to make promising drug targets.

“Developing the database was a labor of love for the Griffiths,” said senior author Richard K. Wilson, PhD, director of The Genome Institute. “There’s an amazing depth to this resource, which will be invaluable to researchers working to design better treatment options for patients.”

Wilson and his colleagues caution that the database is intended for research purposes and that it does not recommend treatments. The primary purpose of the database is to further clinical research aimed at treating diseases more effectively.

“This database gets us one step closer to that goal,” Malachi Griffith said. “It’s a really rich resource, and we’re excited to make it available to the scientific community.”

The database, which took several years to develop, is publicly available and free to use. It includes more than 14,000 drug-gene interactions involving 2,600 genes and 6,300 drugs that target those genes. Another 6,700 genes are in the database because they potentially could be targeted with future drugs.

Before now, researchers wanting to find out whether disease genes could be targeted with drugs had to search piecemeal through scientific literature, clinical trials databases or other sources of information, some of which were not publicly available or easily searchable. Further, many of the existing databases have different ways of identifying genes and drugs, a “language” barrier that can turn a definitive search into an exhaustive exercise.

The Griffith brothers are experts in bioinformatics, a field of science that integrates biology and computing and involves analyzing large amounts of data. The brothers got the idea for the drug-gene interaction database after they repeatedly were asked whether lists of genes identified through cancer genome sequencing could be targeted with existing drugs.

“It shouldn’t take a computer wizard to answer that question,” said Obi Griffith, research assistant professor of medicine. “But in reality, we often had to write special software to find out. Now, researchers can quickly and easily search for themselves.”

The new database brings together information from 15 publicly available databases in the United States, Canada, Europe and Asia. Users can enter the name of a single gene or lists of many genes to retrieve drugs targeting those genes. The search provides the names of drugs targeted to each gene and details whether the drug is an inhibitor, antibody, vaccine or another type. The search results also indicate the source of the information so users can dig deeper, if they choose.

The research is supported by a grant (U54 HG003079) from the National Human Genome Research Institute at the National Institutes of Health (NIH).

Griffith M, Griffith OL, Coffman AC, Weible JV, McMichael JF, Spies NC, Koval J, Das I, Callaway MB, Eldred JM, Miller CA, Subramanian J, Govindan R, Kumar RD, Bose R, Ding L, Walker JR, Larson DE, Dooling DJ, Smith SM, Ley TJ, Mardis ER and Wilson RK. DGIdb – Mining the druggable genome. Nature Methods. Oct. 13, 2013.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare​.

 

October 15, 2013 Posted by | Consumer Health, Medical and Health Research News | , , , , , | Leave a comment

Aspirin to Zoloft: Ways Medicines Work

From the 8 August 2013  US National Library of Medicine article

Most medicines work by binding to and modifying the actions of proteins, tiny molecular machines that perform important cellular tasks. Details about protein structure and function help scientists develop medicines that block proteins or otherwise interact with them. But even when a drug is designed to target a specific protein, it can sometimes impact others, causing side effects. The way medicines work also can be influenced by how a person’s body absorbs and processes them.

Findings from research funded by the National Institutes of Health have shed light on how some common medicines work.

HIV protease with saquinavir.

HIV protease with saquinavir.
View larger image.

Antibiotics, Antivirals

Antibiotics and antiviral drugs attack proteins that are only found in the targeted bacterium or virus and that are crucial for the pathogen’s survival or multiplication. In many cases, the targets are enzymes, which are proteins that speed up chemical reactions. The antibiotic penicillin, for example, hones in on an enzyme that builds bacterial cell walls, causing infecting bacteria to burst and die. Protease inhibitors like saquinavir shut down an enzyme that would otherwise help HIV spread in the body.

Anticancer Agents

Tubulin with taxol.

Tubulin with taxol.
View larger image.

Many anticancer drugs act by killing cells that divide rapidly, but they can also affect healthy dividing cells. For example, paclitaxel (Taxol), which is prescribed for breast, ovarian and other cancers, works by binding to the tubulin protein, inhibiting the formation of structures called microtubules that are needed for cell division. Newer anticancer drugs are more discriminating, often targeting important proteins that are abnormally active in certain cancers. One such drug, imatinib mesylate (Gleevec), halts a cell-communication pathway that is always “on” in a cancer of the blood called chronic myelogenous leukemia. Gleevec’s target is a protein called a kinase, and the drug’s design is based on years of experiments on the basic biology of how cancer cells grow.

Antihistamines, Antidepressants, Aspirin

Adrenergic receptor with carazolol, a beta-blocker.

Adrenergic receptor with carazolol, a beta-blocker. View larger image.

Some of the most widely prescribed drugs function by blocking proteins called G protein-coupled receptors, which play key roles in transmitting the signals that allow a cell to respond to its environment. The drug loratadine (Claritin) relieves allergies by blocking the histamine receptor; antidepressant medications (such as Prozac, Paxil and Zoloft) affect the serotonin receptor; and beta-blockers treat heart disease by interfering with the adrenergic receptor. Signaling can also be stopped by targeting the enzymes that create a molecule involved in the process. This is how aspirin works—it inhibits the enzyme cyclooxygenase, which makes pain-signaling molecules called prostaglandins.

Weight Loss, Cholesterol Blockers

Pancreatic lipase with an inhibitor similar to orlistat.

Pancreatic lipase with an inhibitor similar to orlistat.
View larger image.

Medicines taken to control weight or cholesterol also work by interacting with specific proteins. The weight-loss drug orlistat (Xenical or Alli) blocks the action of pancreatic lipase, reducing the amount of fat that is absorbed from food. Cholesterol-lowering medications, such as atorvastatin (Lipitor) and simvastatin (Zocor), block the action of HMG-CoA reductase, an enzyme involved in making cholesterol.

Future Directions

With a better understanding of the specific relationships between a drug and its target (and off-target) proteins, researchers are using a variety of existing data to identify and test FDA-approved drugs for new uses and to predict potential side effects. This could reduce the time and cost of bringing drugs to market. Scientists are also learning more about how a person’s genes may influence the effectiveness and safety of certain drugs. Another area of active research involves developing new ways to deliver drugs to specific organs or disease sites, also improving therapeutic benefits and reducing side effects.

Content adapted from the poster “How Do Drugs Work?” available from the RCSB Protein Data Bank. Images courtesy of David S. Goodsell, The Scripps Research Institute.

Learn more:

Also in this series:

This Inside Life Science article also appears on LiveScience Link to external Web site.

 

August 25, 2013 Posted by | Educational Resources (High School/Early College(, Health Education (General Public) | , , , , , , , , , , , , | Leave a comment

Solving a traditional Chinese medicine mystery

Solving a traditional Chinese medicine mystery
Discovery of molecular mechanism reveals antitumor possibilities

From the March 3 2011 Eureka news alert

esearchers at the Johns Hopkins School of Medicine have discovered that a natural product isolated from a traditional Chinese medicinal plant commonly known as thunder god vine, or lei gong teng, and used for hundreds of years to treat many conditions including rheumatoid arthritis works by blocking gene control machinery in the cell. The report, published as a cover story of the March issue of Nature Chemical Biology,*** suggests that the natural product could be a starting point for developing new anticancer drugs.

“Extracts of this medicinal plant have been used to treat a whole host of conditions and have been highly lauded for anti-inflammatory, immunosuppressive, contraceptive and antitumor activities,” says Jun O. Liu, Ph.D., a professor of pharmacology and molecular sciences at Johns Hopkins. “We’ve known about the active compound, triptolide, and that it stops cell growth, since 1972, but only now have we figured out what it does.”

Triptolide, the active ingredient purified from the plant Tripterygium wilfordii Hook F, has been shown in animal models to be effective against cancer, arthritis and skin graft rejection. In fact, says Liu, triptolide has been shown to block the growth of all 60 U.S. National Cancer Institute cell lines at very low doses, and even causes some of those cell lines to die. Other experiments have suggested that triptolide interferes with proteins known to activate genes, which gives Liu and colleagues an entry point into their research….

 

***For suggestions on how to get this article for free or at low cost click here

 

 

 

 

March 4, 2011 Posted by | Medical and Health Research News | , , , , | Leave a comment

   

%d bloggers like this: