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 Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>