Featured Research

from universities, journals, and other organizations

Chemists' work will aid drug design to target cancer and inflammatory disease

Date:
August 8, 2013
Source:
Indiana University
Summary:
Chemists have produced detailed descriptions of the structure and molecular properties of human folate receptor proteins, a key development for designing new drugs that can target cancer and inflammatory diseases without serious side effects.

This image shows models of the human folate receptor (top) and antifolate drugs used in chemotherapy (bottom, from left: aminopterin, pemetrexed and methotrexate).
Credit: Charles Dann III / Courtesy of Indiana University

Chemists at Indiana University Bloomington have produced detailed descriptions of the structure and molecular properties of human folate receptor proteins, a key development for designing new drugs that can target cancer and inflammatory diseases without serious side effects.

Related Articles


The researchers, from the lab of Charles Dann III, assistant professor of chemistry in the College of Arts and Sciences, published their findings in the Proceedings of the National Academy of Sciences. Dann said the results should help chemists create more effective antifolate drugs, which act by interfering with the ability of folates -- also called folic acid or vitamin B9 -- to perform tasks that are essential for cell growth.

The findings could be especially helpful against epithelial cell cancers, including ovarian cancers that are resistant to treatment and nearly always fatal. They could also guide the design of drugs for inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriasis.

The article, "Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition," is scheduled to be online this week. Lead author is Soca Wibowo, an IU staff scientist and a former graduate student in Dann's lab. Co-authors include Dann; postdoctoral fellow Mirage Singh; former IU undergraduate researchers Kristen Reeder, Joshua Carter and Alexander Kovach; former IU researchers Wuyi Meng and Faming Zhang; and Manohar Ratnam of the Karmanos Cancer Institute in Detroit.

Physicians have used antifolates for 60 years to treat cancer, and the drugs are often effective at killing cancer cells. The problem is, they aren't selective.

"The antifolates that are currently available also enter normal, healthy cells and kill those as well," Dann said. "What we're describing is an entryway into cancer cells that can be exploited to specifically target or attack cancer cells with drugs."

One reason for the multiple chemotherapeutic side effects of current antifolates is that they typically enter cells via routes that are present in most cell types, not just in cancer cells. The PNAS paper, on the other hand, examines the potential for targeting a different entry route in which the molecules bind with human folate receptors, which are widely present in certain cancer cells and in causal cells of inflammatory disease, but not in normal cells.

Dann describes the folate receptors as "locks" that can be used to open a door into the cell. By gaining a better understanding of what the lock looks like and how it works, researchers can build a better key -- that is, a better antifolate drug -- to open the door.

The lab does this by taking "molecular snapshots" of the folate receptor proteins, capturing the placement of atoms and the origami-like twists and folds of the molecules to reveal how folates and antifolates are likely to bind with the molecules. To understand the structures, the researchers must first convert the receptor proteins to crystals, a complex task that was helped greatly by using the Crystallization Automation Facility in Simon Hall, a recent project of IU's MetaCyt initiative that allows high-throughput crystallography of proteins using advanced robotics.

"The goal is to hit those cells that are causative of disease but not hit the normal cells," Dann said. "For decades, antifolates were all we had for treating certain cancers. Antifolates are great, but we think they can be made better by targeting them to specific cells."

The researchers describe six models to show how antifolates bind with the folate receptors and to examine "biological trafficking" mechanisms that introduce antifolates into cells. The models include the folate receptor in three distinct stages of trafficking and in combination with three antifolates that have been used in clinical settings: pemetrexed, aminopterin and methotrexate.

Dann said evidence suggests the antifolate drugs that have been used to date can bind with the folate receptors but aren't effectively released into the cells -- in effect, the key fits into and jams the lock, making entry impossible. The three-dimensional models of folate receptor proteins should help drug designers create medications that will target, enter and kill cancer cells.

Funding for the research came from the National Institutes of Health and the Indiana University College of Arts and Sciences.


Story Source:

The above story is based on materials provided by Indiana University. Note: Materials may be edited for content and length.


Cite This Page:

Indiana University. "Chemists' work will aid drug design to target cancer and inflammatory disease." ScienceDaily. ScienceDaily, 8 August 2013. <www.sciencedaily.com/releases/2013/08/130808124050.htm>.
Indiana University. (2013, August 8). Chemists' work will aid drug design to target cancer and inflammatory disease. ScienceDaily. Retrieved November 22, 2014 from www.sciencedaily.com/releases/2013/08/130808124050.htm
Indiana University. "Chemists' work will aid drug design to target cancer and inflammatory disease." ScienceDaily. www.sciencedaily.com/releases/2013/08/130808124050.htm (accessed November 22, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Saturday, November 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

WFP: Ebola Risks Heightened Among Women Throughout Africa

WFP: Ebola Risks Heightened Among Women Throughout Africa

AFP (Nov. 21, 2014) Having children has always been a frightening prospect in Sierra Leone, the world's most dangerous place to give birth, but Ebola has presented an alarming new threat for expectant mothers. Duration: 00:37 Video provided by AFP
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Raw: Paralyzed Marine Walks With Robotic Braces

Raw: Paralyzed Marine Walks With Robotic Braces

AP (Nov. 21, 2014) Marine Corps officials say a special operations officer left paralyzed by a sniper's bullet in Afghanistan walked using robotic leg braces in a ceremony to award him a Bronze Star. (Nov. 21) Video provided by AP
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) Researchers find that as people approach new decades in their lives they make bigger life decisions. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins