Navigation Links
Scientists tailor cell surface targeting system to hit organelle ZIP codes
Date:4/17/2012

HOUSTON - Scientists who developed a technology for identifying and targeting unique protein receptor ZIP Codes on the cellular surface have found a way to penetrate the outer membrane and deliver engineered particles - called iPhage - to organelles inside the cell.

In a paper published today online in Nature Communications, the team led by researchers at The University of Texas MD Anderson Cancer Center reports packaging the phage particles with a peptide called penetratin to reach inside the cell.

This new capacity was used to screen for peptide ligands - binding agents - that connect to receptors on mitochondria, which generate a cell's energy, and ribosomes, which process mRNA to make proteins.

The team found a peptide that binds to a specific ribosomal protein called RPL29 which, when delivered with penetratin, disrupts ribosomal function and kills cells. Cell survival was reduced in both malignant and non-malignant cells and in both mouse and human cell lines.

"We provided proof-of-concept for a direct intracellular ligand-receptor screening technology, which is clearly an unmet need in cancer biology, along with the discovery of an organelle ZIP Code that mediates cell death," said Renata Pasqualini, Ph.D., co-senior author of the paper and a professor in MD Anderson's David H. Koch Center for Applied Research of Genitourinary Cancers.

The RPL29 pathway is a new cell death pathway. The researchers found evidence of three types of cell death caused by disrupting the pathway with the new ligand.

"The molecular tool reported here along with its future ramifications will hopefully be of interest to targeted drug development, gene delivery, and mechanisms of human organelle diseases," said Wadih Arap, M.D., Ph.D., also of the Koch Center.

The iPhage screens for ligands inside the cell

Arap and Pasqualini pioneered a screening technique that exploits the existence of unique ZIP Codes in the vascular system to identify molecular targets and the ligands that can be used to selectively hit them.

They developed engineered viral particles, called phage, and packaged them with massive peptide libraries. When injected, these phage/peptide combinations bind to specific receptors in the blood vessels and organs. Cells are then fractionated and analyzed to discover which ligands bind to specific surface proteins.

Arap, Pasqualini and their colleagues have a number of targeted drugs in various stages of development based on screening and then delivery with the combinatorial particles.

The team wondered whether packaging the particles with penetratin, which is known to cross membranes without requiring a cellular receptor, would allow their technology to work inside of cells. "Penetratin makes a little bubble on the cell surface and the bubble goes in through the membrane," Arap said.

They dubbed the combination of penetratin and phage particles "internalizing phage," or iPhage. In a series of experiments, the team found:

  • iPhage successfully entered normal and malignant cells in both mouse and human cell lines while the engineered phage alone, or phage packaged with mutated penetratin, did not gain entry.
  • Connecting iPhage with the mitochondria localization signal (MLS) peptide resulted in a 10-fold concentration of MLS-iPhage in mitochondria compared to simple iPhage, showing that specific organelles could be targeted.
  • To screen for new ligands that might target specific organelles, they attached a random peptide library to iPhage particles and treated the KS1767 cells. Subsequent analysis found the peptide that binds to RPL29.
  • Packaged with penetratin, this "internalizing homing peptide" with the ungainly name YKWYYRGAA killed 75 percent of cells in culture while the peptide alone or penetratin alone killed virtually none.
  • Signs of apoptotic, autophagic and necrotic cell death were found with electron microscopy in cells killed by the YKWYYRGAA-penetratin combination.

Future studies will be needed to understand the complex cell death mechanism caused by the combination.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Scientists identify major source of cells defense against oxidative stress
2. Scientists uncover multiple faces of deadly breast cancer
3. Scientists solving the mystery of human consciousness
4. A*STAR scientists discover special class of natural fats stimulates immune cells to fight diseases
5. Hutchinson Center and TGen scientists discover potential break through in pancreatic cancer
6. Scientists study link between amyloid beta peptide levels and Alzheimers disease
7. Scientists measure how energy is spent in martial arts
8. Scientists link 2 cancer-promoting pathways in esophageal cancer
9. Hutchinson Center scientists break through pancreas cancer treatment barrier
10. Sanford-Burnham scientists unravel cancer drugs secret to resistance
11. Scientists develop a software tool for estimating heart disease risk
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/24/2017)... , ... June 24, 2017 , ... The weather is ... time outdoors. Home and business owners should be aware that the summer months provide ... In fact, mechanical locks and keys can be negatively affected from direct exposure to ...
(Date:6/23/2017)... ... June 23, 2017 , ... The Rhode Island Quality ... Management Alerts and Dashboards, an innovative new service enabling healthcare providers to proactively ... Management Alerts and Dashboards provide near real-time data about patients admitted to and/or ...
(Date:6/23/2017)... , ... June 23, 2017 , ... By scoring 100% ... ninth consecutive four-star rating from premier online charity evaluator, Charity Navigator, validating ANRF's work ... 1% of all charities reviewed by Charity Navigator and earns ANRF a spot on ...
(Date:6/23/2017)... , ... June 24, 2017 , ... Studies show evidence ... reduce the risk of visual loss in these patients. , But how often do ... or smoking cessation to patients at risk of or with early symptoms of AMD? ...
(Date:6/23/2017)... (PRWEB) , ... June 23, 2017 , ... ... plastic surgeon practicing in Newburgh, New York, has recently begun offering three new ... to offering the best cutting-edge procedures and reducing downtime, Dr. Rubinstein is excited ...
Breaking Medicine News(10 mins):
(Date:6/14/2017)...  ivWatch LLC, a medical device company focused on ... is pleased to announce it was the Bronze Winner ... and Equipment at the 2017 Medical Design Excellence Awards ... The award was presented by Medical Device and Diagnostics ... New York during MD&M East, ...
(Date:6/11/2017)... and Company (NYSE: LLY ) announced today ... an investigational treatment for the prevention of episodic and ... endpoints for galcanezumab compared to placebo at both studied ... REGAIN) will be presented today at the American Headache ... . "The detailed Phase 3 ...
(Date:6/8/2017)... Responding to Heath Ledger,s father,s recent call for ... Chris Cornell in May, the mental health watchdog group, ... psychiatric drug side effects search engine ... risks. The father of the late actor ... has called for tighter rules on prescription drugs. Speaking at ...
Breaking Medicine Technology: