One for Wesley

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One for Wesley

Postby TwistedHelix » Fri Nov 09, 2007 7:18 am

Hey Wesley,
I saw this today and thought of you – I seem to recall a little while ago you were going to attend a conference where the subject of the Rho family of proteins was going to be discussed, obviously in relation to cancer. Did anything relevant to MS come up, or did I just miss it? Anyway, here's the abstract:

Zhang Z, Schittenhelm J, Meyermann R, Schluesener HJ.

Institute of Brain Research, University of Tuebingen, Tuebingen, Germany.

Aim: Infiltration of autoantigen-specific T cells and monocytes into the central nervous system is essential for the development of both experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). RhoA is one of the best-known members of Rho GTPases, and inhibition of RhoA has been shown to attenuate the progression of EAE. The aim of this study was to investigate the expression of RhoA in brains of EAE rats and MS tissue. Methods: EAE was induced by immunization with the synthetic peptide gpMBP68-84 in rats, and clinical severity was scored. RhoA expression pattern was investigated in brains of EAE rats at different time points and in different lesions of brain tissue specimens from six MS brains and five neuropathologically unaffected controls by immunohistochemistry. Methods: In EAE rat brains, accumulation of RhoA(+) cells reached maximal levels around Day 13, correlating to the clinical severity of EAE, and up-regulation lasted until the recovery stage of the disease. Double-labelling experiments showed that the major cellular sources of RhoA were reactive macrophages/microglia. While RhoA(+) cells in normal human brain parenchyma were rarely observed, RhoA expression was found to be spatially associated with MS lesions, showing a marked decrease from active lesions via chronic stages to its near absence in normal-appearing white matter. In addition, major RhoA(+) cells in brain parenchyma of MS were identified to be activated macrophages/microglia. Conclusion: Our present data indicated that RhoA may play an important role during the effector phase of EAE and MS. Therefore, RhoA inhibitors might be a therapeutic option for MS patients.

PMID: 17983427 [PubMed - as supplied by publishe
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Postby BioDocFL » Fri Nov 09, 2007 3:24 pm

One of our drug discovery projects is looking for inhibitors of RhoGEFs. GEF stands for GTP Exchange Factor. Rho proteins, like RhoA, are involved in cell signalling cascades. The Rho binds GTP (guanosine triphosphate) and uses one phosphate to modify another protein, leaving GDP (guanosine diphosphate) bound to the Rho. To recharge the Rho with a new GTP, a GEF will bind the Rho and cause a change in Rho that releases the GDP and opens things up for a new GTP. We are trying to find inhibitors of the Rho and GEF interaction. This is a protein-protein interaction so it is larger surface areas coming together that we are trying to disrupt. Finding small molecules to disrupt these larger interactions is more difficult than finding a small molecule to inhibit the (smaller) active site of an enzyme. One approach is a combinatorial method where you find two or more very small molecules that bind the interface close to each other and then figure out how to link them into one larger molecule. Another approach is to find peptide mimetics, i.e. a molecule mimicking a few of the amino acids of one of the two interacting proteins. That might disrupt the interaction. You can't use the actual amino acids since it will probably be degraded by the cell.
So, if we find one or more small molecules that can inhibit the protein-protein interactions in an in vitro (test tube) experiment, we then need to see if they can get into the cells to do their job. And we need to make sure that is all they are disrupting because we don't want normal cells to suffer too much from the drug.
This is all towards cancer therapy but, once we find something and publish it, others who are looking at RhoGEFs for other diseases can use our findings towards their cell lines that model their disease.
I was at a symposium a few weeks ago listening to a speaker from Abbott Laboratories who is working on a protein similar to one of our other projects. Abbott a year ago had been kind enough to give us a sample of their second best drug candidate towards that protein so we could use it as a control in our own testing. The talk was about a better one they have since found and the speaker said they had given samples of the second best one freely to over 100 research groups besides us. I think they should be applauded for their generosity and I think other researchers are starting to be a little more open on sharing, after they get a patent established on their most promising leads of course. It does help to remove redundant efforts and it helps improve the quality of research overall. In the case of the RhoGEF project, we have a collaboration going with two other universities and we are sharing our protocols and we are using our robotics to help test their focused libraries (a bunch of variants built around one basic small molecule structure of interest). So, although my main interest is autoimmune diseases, I feel I can be productive towards autoimmune diseases while working on cancer projects. Among our cancer projects I have been working on S-adenosylmethionine decarboxylase (an enzyme involved in polyamine synthesis) and RhoGEFs.
So that is two projects that appear to have potential in both cancer and autoimmune diseases. I imagine I'll run across the parallels in other projects too. Thanks for pointing out the article.

Wesley
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