Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Light activated 'warhead' turns modest molecules into super protein killers

15.03.2010
Novel research tool from Scripps Florida could significantly expand search for new therapies

Using a novel light activation technique, Scripps Research Institute scientists have been able to turn molecules with only a modest ability to fight specific proteins into virtual protein destroyers.

The new technique, which uses a "warhead" molecule capable of inactivating nearby proteins when triggered by light, could help to accelerate the development of new therapies by providing researchers with a new set of research tools and options.

The study was published March 14, 2010 in an advanced, online edition of the journal Nature Chemical Biology.

"High-throughput screening can produce a synthetic ligand [peptoid] capable of binding to just about any protein you want," said Thomas Kodadek, a professor in the Department of Chemistry at the Institute's Jupiter, Florida, campus, who led the study. "The problem is, they almost always have modest potency – which makes them less than ideal research tools. By attaching this 'warhead' molecule to a peptoid, we've shown that we can increase that protein-killing potency by a thousand fold without going through an expensive and time-consuming optimization process."

The new technique offers researchers rapid access to some very potent, very selective light activated compounds that can knock out specific protein function, an important strategy in research into diseases such as cancer. Since light can be focused with high spatial resolution, this technology may open the door for knocking out proteins in only one region of a single cell, but not another, allowing, for example, the inactivation of a target protein in the nucleus, but not in the cytoplasm that surrounds it.

A Choice of Warheads

The technique is known as a CALI, which stands for chromophore-assisted light inactivation; chromophores are molecules that can absorb visible or ultraviolet light. While other researchers have made CALI reagents previously, they suffered from poor efficiency, largely due to self-inactivation. The new warhead used by the Scripps Florida team represents a significant advance.

They used a derivative of ruthenium, a metallic element that produces what is known as singlet oxygen, the well known oxygen molecule, O2.

"When the ruthenium absorbs visible light," Kodadek said, "it has to dump that energy to return to a normal state. In the process, it produces an extremely reactive form of oxygen that rips apart whatever proteins it happens to encounter. Basically, it destroys those proteins forever."

While there have been reports of other "warhead"-carrying peptoids, the study said, the ruthenium derivative used by Kodadek and his colleagues is an important technical advance, one that allows scientists to target both extracellular and intracellular protein targets. Unlike organic singlet oxygen generators, the Ru complex is itself insensitive to singlet oxygen, greatly increasing the efficiency of CALI.

The other important point, the study noted, is that these new peptoids have no effect on any cellular components until they are activated by light.

Simple synthetic compounds like peptoids have many advantages over other ligands – molecules that bind to proteins and alter their function – such as antibodies, Kodadek pointed out. They can be modified easily for attachment to surfaces and can be produced relatively quickly in large amounts – a multi-million member peptoid library, for example, can be created in about three days.

This makes them ideal building tools for biomedical research, the study said.

Kodadek became interested in developing this new technique when he and Benjamin Cravatt, chair of the Scripps Research Department of Chemical Physiology, decided to combine separate technologies – a peptoid library synthesis and screening platform developed in the Kodadek laboratory in Florida and activity-based protein profiling (ABPP) developed in Cravatt's laboratory in California. The combination offered a powerful new method of screening and identifying more high quality lead drug candidates.

"But when we first had this idea to collaborate to identify hundreds of protein ligands simultaneously, my enthusiasm was diminished by the fact that I knew they would all be modest potency compounds and the numbers would overwhelm our ability to optimize them all by traditional means," Kodadek said. "Our new 'warhead' technique solves that problem."

The first author of the study, "Potent and Selective Photo-inactivation of Proteins with Peptoid-Ruthenium Conjugates," is Jiyong Lee of the University of Texas Southwestern Medical Center and Scripps Research. In addition to Kodadek, other authors include D. Gomika Udugamasooriya of the University of Texas Southwestern Medical Center and Hyun-Suk Lim of University of Texas Southwestern Medical Center and the Indiana University School of Medicine.

The study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.

For information:
Keith McKeown
858-784-8134
kmckeown@scripps.edu

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>