The Synaptic Leap

There may be members of this community who do not yet have direct experience of developing a new medicine from concept to pharmacy shelf.  Be assured, there is a lot more to it than "just" the synthesis of the API.  Why not take advantage of a Free ACS Webcast on May 6, 2010 Thurs 2:00-3:00 PM ET
From a Beaker to a Bottle: Overview of the Drug Discovery and Development Process for Small Molecule Therapeutics
A free webcast from the American Chemical Society as part of their Professional Growth and Development Series. Learn about the drug development process and find out how long it takes, how much it costs, and the odds of getting a new drug approved.

Hi all,

I would like to introduce my open-source project at Stanford, GemIdent:

http://www.gemident.com

http://en.wikipedia.org/wiki/GemIdent

GemIdent specializes in color image segmentation using supervised machine learning. For example, you can use it to locate and count cells in microscopic images:

GemIdent in action identifying cancer cells in a IHC-stained lymphnode image

There's a new database from WHO for tracking new targets for drug discovery for neglected diseases. Not much there yet, but it's sure to grow.

Mat

On a proposé Hydroxyurea comme traitement possible pour la toxoplasmose.

À cet effet, j'avais essayer trouver quelquechose qu'on pourrait employer -- ou qu'un docteur, s'occupant des patients sans les ressources financières, pourrait employer, au lieu des drogues indisponibles de prescription.

J'ai trouvé une usine. L'herbe « romarin » Rosmarinus officinalis).

Alors . . . combien de fois l'agneau c'est servi rare?  Il semble, toujours.  Avec de la sauce à romarin.

C'est un antidote immédiat?  Que pensez-vous?

Hydroxyurea is a possible treatment for toxoplasmosis:

FEMS Microbiol Lett. 2000 Apr 1;185(1):79-82. Hydroxyurea inhibits intracellular Toxoplasma gondii multiplication. de Melo EJ, Mayerhoffer RO, de Souza W.

With this in mind, I went looking to see if there were anything that an average person might use -- or that a doctor, caring for patients with no financial resources, might use, in lieu of unavailable prescription drugs.

One thing did turn up.  Rosemary, the herb, the plant (Rosmarinus officinalis L. - Lamiaceae).  It contains 3-BETA-HYDROXYUREA-12,20(30)-DIEN-17-ON-ACID. 

Sodium butyrate is an HDAC inhibitor -- very early & very recent cites --

J Biol Chem. 2007 Mar 30;282(13):9797-804. Epub 2007 Jan 24.Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate.
Stempelj M, Kedinger M, Augenlicht L, Klampfer L.

Cell. 1978 May;14(1):105-13. Sodium butyrate inhibits histone deacetylation in cultured cells.  Candido EP, Reeves R, Davie JR.

Dear TSL Members,

You are invited to the first annual QB3-UCSF-CDD developing world disease research community meeting scheduled for March 5^th 2007 at the UCSF Mission Bay Campus (details below and attached).  The collaborative community includes leading experts on developing world infectious disease research from Stanford, UCSF, UC Berkeley, UCLA, UW, SBRI, St. Jude CRH, U. Penn, Univ. of Sydney, and industry too.  

Collaborative Drug Discovery
First Annual Community Meeting

Monday, March 5^th 2007 1:00-6:00 pm; Auditorium: J. David Gladstone Institute (1^st Floor)

Hosted by Gladstone Institute and QB3 at the UCSF, Mission Bay Campus

Two major themes of this event are:

1)      Public-Private-Partnerships for Global Health Issues
2)      “Open” concepts for Collaborative Drug Discovery

Confirmed Speakers:
 

• Dr. Christopher Lipinski, Pfizer, retired. (Keynote presentation)
  
• Jim McKerrow, Professor, Dept. of Pathology, QB3 - UCSF
  
• Matt Bogyo, Professor, Dept. of Pathology, Stanford Medical School
  
• Andrej Sali, Professor, Dept of Biopharmaceutical Sciences, QB3 - UCSF
  
• Dr. Anang Shelat, St. Jude Children’s Research Hospital
  
• David Roos, Biology Professor, Univ. of Penn tentatively confirmed (Director, Penn Genomics Institute).

Symposium – Coffee/Snacks – Demos – Posters – Networking – Wine Reception

Registration is free. To register contact/RSVP to: kgregory@collaborativedrug.com.

Histone acetyltransferases (HATs) and HAT inhibitors
The significance of studying HATs is underscored by an abundance of genetic studies that implicate them in having a role in disease (for reviews, see (10), (6), and (16)).  Consistent with this, some histone deacetylase (HDAC) inhibitors display anti-tumor activity and are being evaluated in clinical trials (8).  In addition to regulating transcription, HATs have crucial functions in modulating other DNA processes (7).  Histone acetylation machinery may also be a viable target for novel anti-infectives (5).
The impact of the various HATs on cellular physiology and disease would greatly benefit from the identification of specific pharmacological inhibitors, but very few have been described to date (11).  Two natural products, anacardic acid and garcinol (a polyprenylated benzophenone), are reported to inhibit both p300/CBP and PCAF in a 5-10 mM range in vitro (1, 2).  In contrast, curcumin displays activity against p300/CBP, but not PCAF (3).  Subsequent studies suggest that anacardic acid may be a broad-spectrum HAT inhibitor, as it also interferes with the MYST HAT Tip60 (13).  Isothiazolones were identified in a high-throughput screen as inhibitors of PCAF and p300 (12), but like the aforementioned compounds, activity against GCN5 was not determined.  Moreover, isothiazolones are strongly reactive with thiol groups and hence are likely to have substantial nonspecific effects.  Two small molecule inhibitors of GCN5 that have been documented include a butyrolactone (4) and MC1626 (2-methyl-3-carbethoxyquinoline) (9).  However, in our hands, the butyrolactone and MC1626 exhibit no inhibition of recombinant yeast GCN5 in a standard in vitro HAT assay (Sullivan, unpublished).  As a positive control, parallel HAT assays showed anacardic acid does inhibit yeast GCN5.
Two reports describe systems that can be used in high-throughput format to identify potential HAT inhibitors (14, 15).
We are interested in acquiring HAT inhibitors, especially those that appear to be selective for distinct types of HATs (i.e. GCN5, MYST).  Not only would these serve as valuable probes to study histone acetylation in eukaryotic cells, they may also hold promise as novel drugs to combat parasitic disease.
References

Welcome, I am Bill Sullivan, the online leader for The Synaptic Leap’s Toxoplasma research community. You can find out more about my work at the laboratory web site.

Why Toxoplasma is important

Toxoplasma gondii is a protozoan (single-celled) parasite that has permanently infected tens of millions of people in the world.  A normal immune response typically controls infection promptly, but the parasite persists as a latent cyst within host tissues.  Tissue cysts can form in brain, heart, and skeletal muscle tissue.  If immunity should become compromised due to disease (such as AIDS) or immunosuppressive therapies (e.g., cancer chemotherapy or organ transplantation), the acute stage of infection may recrudesce.  Thus, Toxoplasma is a significant opportunisitc pathogen.  However, there are instances when Toxoplasma threatens normal, healthy individuals as well.  For example, Toxoplasma can cause abortion or congenital birth defects; this may occur if a woman becomes infected for the first time during pregnancy.  Additionally, emerging studies have demonstrated intriguing alterations in host organism behavior upon infection, or correlations with neurological disorders such as schizophrenia.

Toxoplasma infection may be picked up from cats (the definitive host) or contaminated food/water.  People at significant risk (HIV+ or pregnant individuals) should cook meat thoroughly, wash vegetables, and avoid cat litter boxes and gardening.