NJIT professor develops biologically-inspired catalysis active, yet inert materials

NJIT Associate Professor Sergiu M. Gorun is leading a research team to develop biologically-inspired catalysis active, yet inert, materials. The work is based on organic catalytic framework made sturdy by the replacement of carbon-hydrogen bonds with a combination of aromatic and aliphatic carbon-fluorine bonds. Graduate students involved with this research recently received first place recognition at the annual NJIT Dana Knox student research showcase.

The newest focus of Gorun's research has been the cobalt complex as a catalyst for which the known degradation pathways appear to have been suppressed. "Broadening the Reactivity Spectrum of a Phthalocyanine Catalyst While Suppressing Its Nucleophilic, Electrophilic and Radical Degradation Pathways" by Gorun and others appeared in the web issue of Dalton Transactions (2011), ASAP Communication. Similar to a previous publication, this recent one addresses an important industrial process, the "sweetening" of petroleum products by the transformation of smelly and corrosive thiols into disufides. The extreme electronic deficiency of the new catalyst metal center allows it to process molecules that are not reactive in the presence of regular catalysts that perform this chemistry industrially.

Two years ago Gorun and his team reported that the related zinc perfluoroalkylated phthalocyanine, a molecule resembling the porphyrin core of several heme enzymes, exhibit highly-efficient photochemical oxygenation of an organic substrate. This was of great interest to the fragrance industry ("Rational design of a reactive yet stable organic-based photocatalyst" Dalton Transactions, 2009, 1098).

Concurrently, the unusual properties of Gorun's new materials are explored in parallel in constructing surface coatings, an area in which Gorun was awarded US patent 7,670,684. Several publications describe the properties of the new coatings.

More information: DOI: 10.1039/C1DT10458F

Provided by New Jersey Institute of Technology

Discovery of relationship between proteins may impact development of cancer therapies

By identifying a surprising association of two intracellular proteins, University of Iowa researchers have laid the groundwork for the development of new therapies to treat B cell lymphomas and autoimmune disease.

The researchers studied mouse B cells expressing the viral protein Latent Membrane Protein 1 (LMP1), which has been implicated in several types of cancer because of its role in the proliferation and survival of Epstein-Barr virus infected B cells. They discovered that LMP1 needs the cellular protein Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) to promote its B cell activation signaling pathways.

The study, published recently in the Journal of Biological Chemistry, also shows that LMP1 and CD40 – a normal activating receptor of B cells – both use TRAF6 as a key signaling protein, but in different ways. LMP1 mimics CD40 in delivering activation signals to B cells, but LMP1's signals are amplified and sustained, resulting in B cell hyper-activation.

B cells are a type of white blood cell. They normally mature into plasma cells that produce proteins called antibodies necessary to fight off infections. But in the process of modifying antibody genes, mistakes can cause mutations. With an accumulation of such mutations, B cells can become cancerous, which is why B cell malignancies are relatively common.

"We found that TRAF6 is essential for LMP1 functions, and that it interacts with LMP1 in a way that is distinct from the way in which TRAF6 interacts with CD40," said lead author Kelly Arcipowski, a Ph.D. candidate in the UI Molecular and Cellular Biology Interdisciplinary Graduate Program. "Thus, it might be possible to target LMP1 signaling without disrupting normal immune function. This information is valuable to the development of new therapies to target LMP1-mediated pathogenesis, including B cell lymphomas and autoimmune disease."

B-cell lymphomas include Hodgkin's lymphomas and most non-Hodgkin's lymphomas. Examples of autoimmune diseases in which LMP1 is implicated are rheumatoid arthritis and systemic lupus erythematosus (SLE).

LMP1 is produced by a normally latent gene that is expressed when Epstein-Barr virus, a herpes virus that infects greater than 90 percent of humans, becomes reactivated from its inactive state. This can occur in flares of autoimmune disease, and in people who are immune-deficient. Epstein-Barr virus can thus become activated in cases of late-stage AIDS or organ and bone marrow transplant recipients who are immunosuppressed to prevent rejection of the transplant.

While LMP1 contributes to the formation of a tumor, it isn't an ideal target for therapeutics. LMP1 is a protein that is being constantly internalized from the cell surface, prompting researchers to instead target the signaling pathway.

"(Researchers) first thought you would be targeting the normal protein (CD40), too," said senior study author Gail Bishop, Ph.D., professor of microbiology at the UI Carver College of Medicine and director of the Immunology Interdisciplinary Graduate Program. "What our lab has discovered over the years is that LMP1 produces CD40-like effects using the same proteins in different ways, and therefore that opens a window to targeting just LMP1."

Arcipowski currently is researching how TRAF6 is activating the LMP1 signaling pathway.
"If you figured out exactly which part of TRAF6 was binding to LMP1, you could target that specific interaction while leaving TRAF6's association with CD40 intact," Arcipowski said.

Provided by University of Iowa Health Care

Biophysicist targeting IL-6 to halt breast, prostate cancer

An Ohio State biophysicist used a supercomputer to search thousands of molecular combinations for the best configuration to block a protein that can cause breast or prostate cancer.

Chenglong Li, Ph.D., an assistant professor of medicinal chemistry and pharmacognosy at The Ohio State University (OSU), is leveraging a powerful computer cluster at the Ohio Supercomputer Center (OSC) to develop a drug that will block the small protein molecule Interleukin-6 (IL-6). The body normally produces this immune-response messenger to combat infections, burns, traumatic injuries, etc. Scientists have found, however, that in people who have cancer, the body fails to turn off the response and overproduces IL-6.

"There is an inherent connection between inflammation and cancer," explained Li. "In the case of breast cancers, a medical review systematically tabulated IL-6 levels in various categories of cancer patients, all showing that IL-6 levels elevated up to 40-fold, especially in later stages, metastatic cases and recurrent cases."

In 2002, Japanese researchers found that a natural, non-toxic molecule created by marine bacteria – madindoline A (MDL-A) – could be used to mildly suppress the IL-6 signal. Unfortunately, the researchers also found the molecule wouldn't bind strongly enough to be effective as a cancer drug and would be too difficult and expensive to synthesize commercially. And, most surprisingly, they found the bacteria soon mutated to produce a different, totally ineffectual compound. Around the same time, Stanford scientists were able to construct a static image of the crystal structure of IL-6 and two additional proteins.

Li recognized the potential of these initial insights and partnered last year with an organic chemist and a cancer biologist at OSU's James Cancer Hospital to further investigate, using an OSC supercomputer to construct malleable, three-dimensional color simulations of the protein complex.

"The proximity of two outstanding research organizations – the James Cancer Hospital and OSC – provide a potent enticement for top medical investigators, such as Dr. Li, to conduct their vital computational research programs at Ohio State University," said Ashok Krishnamurthy, interim co-executive director of OSC.

"We proposed using computational intelligence to re-engineer a new set of compounds that not only preserve the original properties, but also would be more potent and efficient," Li said. "Our initial feasibility study pointed to compounds with a high potential to be developed into a non-toxic, orally available drug."

Li accessed 64 nodes of OSC's Glenn IBM 1350 Opteron cluster to simulate IL-6 and the two additional helper proteins needed to convey the signal: the receptor IL-6R and the common signal-transducing receptor GP130. Two full sets of the three proteins combine to form a six-sided molecular machine, or "hexamer," that transmits the signals that will, in time, cause cellular inflammation and, potentially, cancer.

 

An electrostatic representation (red: negative; blue: positive; white: hydrophobic) created at the Ohio Supercomputer Center by Ohio State?s Chenglong Li, Ph.D., shows IL-6 in ribbon representation. The two larger yellow ellipses indicate the two binding "hot spots" between IL-6 and GP130, key to blocking a protein that plays a role in breast and prostate cancer. Credit: Chenglong Li/OSU

Li employed the AMBER (Assisted Model Building with Energy Refinement) and AutoDock molecular modeling simulation software packages to help define the interactions between those proteins and the strength of their binding at five "hot spots" found in each half of the IL-6/IL-6R/GP130 hexamer.

By plugging small molecules, like MDL-A, into any of those hot spots, Li could block the hexamer from forming. So, he examined the binding strength of MDL-A at each of the hexamer hotspots, identifying most promising location, which turned out to be between IL-6 and the first segment, or modular domain (D1), of the GP130.

To design a derivative of MDL-A that would dock with D1 at that specific hot spot, Li used the CombiGlide screening program to search through more than 6,000 drug fragments. So far, he has identified two potential solutions by combining the "top" half of the MDL-A molecule with the "bottom" half of a benzyl molecule or a pyrazole molecule. These candidates preserve the important binding features of the MDL-A, while yielding molecules with strong molecular bindings that also are easier to synthesize than the original MDL-A.

"While we didn't promise to have a drug fully developed within the two years of the project, we're making excellent progress," said Li. "The current research offers us an exciting new therapeutic paradigm: targeting tumor microenvironment and inhibiting tumor stem cell renewal, leading to a really effective way to overcome breast tumor drug resistance, inhibiting tumor metastasis and stopping tumor recurrence."

While not yet effective enough to be considered a viable drug, laboratory tests on tissue samples have verified the higher potency of the derivatives over the original MDL-A. Team members are preparing for more sophisticated testing in a lengthy and carefully monitored evaluation process.

Li's project is funded by a grant from the Department of Defense (CDMRP grant number BC095473) and supported by the award of an OSC Discovery Account. The largest funding areas of Congressionally Directed Medical Research Programs (CDMRP) are breast cancer, prostate cancer and ovarian cancer. Another Defense CDMRP grant involving Li supports a concurrent OSU investigation of the similar role that IL-6 plays in causing prostate cancer. Those projects are being conducted in collaboration with Li's Medicinal Chemistry colleague, Dr. James Fuchs, as well as Drs. Tushar Patel, Greg Lesinski and Don Benson at OSU's College of Medicine and James Cancer Hospital, and Dr. Jiayuh Lin at Nationwide Children's Hospital in Columbus.

"In addition to leading the center's user group this year, the number and depth of Dr. Li's computational chemistry projects have ranked him one of our most prolific research clients," Krishnamurthy noted.

Provided by Ohio Supercomputer Center

Toward new medications for chronic brain diseases

A needle-in-the-haystack search through nearly 390,000 chemical compounds had led scientists to a substance that can sneak through the protective barrier surrounding the brain with effects promising for new drugs for Parkinson's and Huntington's disease. They report on the substance, which blocks formation of cholesterol in the brain, in the journal, ACS Chemical Biology.

Aleksey G. Kazantsev and colleagues previously discovered that blocking cholesterol formation in the brain could protect against some of the damage caused by chronic brain disorders like Parkinson's disease. Several other studies have suggested that too much cholesterol may kill brain cells in similar neurodegenerative diseases. So they launched a search for a so-called "small molecules" — substances ideal for developing into medicines — capable of blocking formation of cholesterol.

They describe discovery of a small molecule that blocks the activity of a key protein involved in cholesterol production. It successfully lowered cholesterol levels in isolated nerve cells and brain slices from mice. If the molecule proves to be a good target for developing new drugs, the scientists note, "it could have a broader application in other neurological conditions, such as Alzheimer's disease, for which modulation of cholesterol and other associated metabolic pathways might be of therapeutic benefit."

Provided by American Chemical Society (news : web)