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 Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology

nachricht Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Frictional Heat Powers Hydrothermal Activity on Enceladus

Computer simulation shows how the icy moon heats water in a porous rock core

Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Underwater acoustic localization of marine mammals and vehicles

23.11.2017 | Information Technology

Enhancing the quantum sensing capabilities of diamond

23.11.2017 | Physics and Astronomy

Meadows beat out shrubs when it comes to storing carbon

23.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>