Friday, January 25, 2008

We Have Anti-Malarial Activity!

The results are in.

Jiri Gut from the Rosenthal group has run 2 of our Ugi products and they both show inhibition of falcipain-2 (EXP165) and Plasmodium falciparum (EXP166) in the micromolar range.

To put this in context the activities are roughly 2 orders of magnitude lower than the positive control used for the enzyme inhibition and chloroquine for the parasite.

But it is a start. And we have officially closed the Open Science Loop for the malaria project, meaning that we have openly documented the docking results from Rajarshi Guha (D-EXP014), our syntheses (EXP148 EXP150) and testing (EXP165 EXP166) in the Rosenthal group.

We can't tell much about the validity of Rajarshi's docking model from the results of two compounds but as more data come in the situation should become clearer.

However, Jiri did make this interesting observation:
The food vacuole abnormality, which is indicative of cysteine protease inhibition was not observed in the parasites, suggesting other mode of action.

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At 8:10 PM, Blogger Rajarshi said...

Woo hoo!

Are you planning to optimize thse structures? Also, how many did you send out for assay?

At 11:29 PM, Blogger Bill Hooker said...

Awesome, Jean-Claude. Just awesome. From concept to lead compounds in a matter of months.


At 4:53 AM, Blogger Cameron Neylon said...

Brilliant news! It would be great to see the loop go around again as well but its great as Bill says to see this really happen.

At 6:41 AM, Blogger Jean-Claude Bradley said...

Those 2 are the only ones we sent out so far - the status of any compound submitted for testing will be maintained here:
As for optimization, I am hoping for advice from the experts (like you :) in the drug development community. (How well that will work is part of the experiment of Open Notebook Science).
I got some very helpful input from my recent visit at NIH about formulation that I will incorporate shortly. But otherwise, until we hear differently, we're going to continue to make the top molecules in the libraries you provided for us.
The bottleneck right now is making the molecules - we just need more student-hours in the lab.

Thanks! Indeed we have a long way to go but this was an important milestone for us.

At 7:06 AM, Blogger Cameron Neylon said...

Yes, the problem is always the pairs of hands available. Just had a chance to look at the pages themselves. It would be really good to see the raw data for the fluorescence and FACS measurements. I'm interested in this from the perspective of how arbitrary data can go into the Blogger system and what it looks like on RSS feeds etc.

Also it would be great to see how the professionals do their FACS measurements. As chemists we struggle with these kind of assays because we don't have the experience.

At 10:55 AM, Blogger Gus Rosania said...

Great! It would be good for us to see some SAR around these structures: a set of related compuonds with slight modifications that render them inactive (it would point to the parts of the molecules essential for activity).

For lysosomal targeting (assuming these are acting against a lysosomal target, which is largely an assumption at this point), incorporating one or two amines would be nice at a site that does not interfere with the molecules' molecular activity .

Once an amine can be incorporated, then ion trapping can be tailored in to maximize lysosomal accumulation. We can fine tune lysosomal vs. mitochondrial vs. other accumulations with modeling work...but just getting one (or two?) amines on the molecules at a site that does not interfere with the molecular mechanism of action would tell us what is feasible, in terrms of how to proceed (from a chemical synthesis and site of action perspective).

At 11:48 AM, Blogger Jean-Claude Bradley said...

Gus that is good feedback. Another good reason for incorporating an amine is to make a water soluble salt. I'll take a look at the libraries we can make with tertiary amine groups somewhere. Primary or secondary amines are out because they would participate in the Ugi reaction. Another option is to use boc-protected amino acids then use a convenient deprotection procedure.


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