Featured Research

from universities, journals, and other organizations

New peptides to fight ovarian cancer drug resistance

Date:
August 1, 2011
Source:
Heidelberg Institute for Theoretical Studies
Summary:
Italian and German scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug resistant ovarian cancer cells.

Structure of human thymidylate synthase with an inhibitory peptide bound at its dimer interface determined by x-ray crystallography. The protein is shown with a cartoon representation of its secondary structure colored according to sequence and the peptide is colored by atom-type with its electron density contoured in blue.
Credit: Cardinale et al.

Italian and German scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug resistant ovarian cancer cells. The interdisciplinary research project was led by the University of Modena and Reggio Emilia (UNIMORE) and the Heidelberg Institute for Theoretical Studies (HITS).

Related Articles


Worldwide, over 200,000 women are diagnosed with ovarian cancer every year, with higher incidence in developed countries where it is the fifth leading cause of cancer-related deaths in women. Ovarian cancer has a high mortality rate due to frequent late diagnosis and the rapid development of drug resistance. Several clinically important anti-cancer drugs that are widely used in chemotherapy inhibit the enzyme, thymidylate synthase, which plays a key role in DNA synthesis. However, the use of these drugs is associated with drug resistance and new compounds with different inhibitory mechanisms are required to combat resistance.

Scientists from Italy and Germany have designed octapeptides that specifically target the protein-protein interface of thymidylate synthase. Thymidylate synthase is composed of two identical polypeptide chains, i.e. it is a homodimer. The peptides stabilize the inactive form of the enzyme, show a novel mechanism of inhibition for homodimeric enzymes, and inhibit cell growth in drug sensitive and resistant cancer cell lines.

The interdisciplinary collaboration between scientists in Italy and Germany, led by Maria Paola Costi and Glauco Ponterini at the University of Modena and Reggio Emilia, Stefano Mangani at the University of Siena (UNISI) and Rebecca Wade at Heidelberg Institute for Theoretical Studies (HITS), was part of the LIGHTS project (LIGands to interfere with human TS). The project was supported by the Sixth Framework Programme (FP6), an EU scheme to fund and promote European research and technological development.

The researchers have discovered several peptides that inhibit thymidylate synthase by modulating protein-protein interactions. Maria Paola Costi explains: "These peptides have sequences from the protein-protein interface of the enzyme and inhibit it by binding to a previously unknown allosteric binding site -- that is, a site other than the protein's active site -- at the protein-protein interface." By a combination of experimental and computational approaches, it was shown that their inhibitory mechanism involving stabilization of an inactive form of the catalytic protein differs from those of protein-protein interface inhibitors reported to date.

Unlike the existing drugs targeting thymidylate synthase, these peptides inhibit intra-cellular thymidylate synthase and cell growth without leading to increased levels of thymidylate synthase protein when administered to ovarian cancer cells. "This observation indicates the potential value of these peptides in overcoming drug resistance problems, although the cellular effects remain to be fully explored," says Rebecca Wade. Further steps will require optimization of the compounds discovered and detailed analysis of their cellular mechanism of action. The concepts revealed by this work can be expected to provide new avenues for the development of drugs for combating diseases such as ovarian cancer.


Story Source:

The above story is based on materials provided by Heidelberg Institute for Theoretical Studies. Note: Materials may be edited for content and length.


Journal Reference:

  1. D. Cardinale, G. Guaitoli, D. Tondi, R. Luciani, S. Henrich, O. M. H. Salo-Ahen, S. Ferrari, G. Marverti, D. Guerrieri, A. Ligabue, C. Frassineti, C. Pozzi, S. Mangani, D. Fessas, R. Guerrini, G. Ponterini, R. C. Wade, M. P. Costi. Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1104829108

Cite This Page:

Heidelberg Institute for Theoretical Studies. "New peptides to fight ovarian cancer drug resistance." ScienceDaily. ScienceDaily, 1 August 2011. <www.sciencedaily.com/releases/2011/08/110801121906.htm>.
Heidelberg Institute for Theoretical Studies. (2011, August 1). New peptides to fight ovarian cancer drug resistance. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2011/08/110801121906.htm
Heidelberg Institute for Theoretical Studies. "New peptides to fight ovarian cancer drug resistance." ScienceDaily. www.sciencedaily.com/releases/2011/08/110801121906.htm (accessed November 28, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Friday, November 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola Leaves Orphans Alone in Sierra Leone

Ebola Leaves Orphans Alone in Sierra Leone

AFP (Nov. 27, 2014) — The Ebola epidemic sweeping Sierra Leone is having a profound effect on the country's children, many of whom have been left without any family members to support them. Duration: 01:02 Video provided by AFP
Powered by NewsLook.com
Experimental Ebola Vaccine Shows Promise In Human Trial

Experimental Ebola Vaccine Shows Promise In Human Trial

Newsy (Nov. 27, 2014) — A recent test of a prototype Ebola vaccine generated an immune response to the disease in subjects. Video provided by Newsy
Powered by NewsLook.com
Pet Dogs to Be Used in Anti-Ageing Trial

Pet Dogs to Be Used in Anti-Ageing Trial

Reuters - Innovations Video Online (Nov. 26, 2014) — Researchers in the United States are preparing to discover whether a drug commonly used in human organ transplants can extend the lifespan and health quality of pet dogs. Video provided by Reuters
Powered by NewsLook.com
Today's Prostheses Are More Capable Than Ever

Today's Prostheses Are More Capable Than Ever

Newsy (Nov. 26, 2014) — Advances in prosthetics are making replacement body parts stronger and more lifelike than they’ve ever been. 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