30 March 2015

Politburo Approved

Viral, tropical diseases are really cool because they have great names. e.g. Dengue or Breakbone Fever or Chikungunya ("that which breaks up").  The great thing about many viral diseases is that they are dependent upon proteases for many things. (And yes, I know how that sounds.)  Proteases have nice, well defined active sites that you can fill quite well and shut them down. In this paper, the authors use fragment-peptide merging to inhibit Dengue protease.  

This is really an extension of previous work.  The original work used capped peptides with a warhead with very good potency (down to 43 nM).  They then investigated retro, retro-inverse, semiretro-inverse, and nonretro di- and tri-peptides.  This lead them to use a tri-peptide (Arg-Lys-Nle) in two generations: first an arylcyanoacrylamide and then to N-substituted 5-arylidenethiazolidinone (thiazolidinediones and rhodanines).  These second generation hybrids had increased membrane permeability, in vitro binding, in cellulo antiviral activity.  Based on docking, they decided to investigate Nle sitting in P1', in contrast to previous site preferences and then merge it with fragments from an optimized capping moiety. 
1.  Starting Point Hybrid Peptide
The investigation of Nle replacements led to the phenylglycine molecule, with 4x greater affinity:
9.  Phenyl-glycine hybrid
They, then chose three hybrids (including 9) and put two different caps on them:
Rhodanine Cap
Acrylamide cap

Compared to the benzoyl cap, the acrylamide was 2x better while the rhodanine was 5x better.  But, wait, doesn't the Politburo condemn all uses of rhodanines?  Of course not.  In this case, the rhodanine was selected through rigorous analysis: and they have selectivity (this assay is fluorogenic).  They are perfectly aware of the general distaste people have for rhodanines and address the concerns. All of this together, leads to the final compound (below).
This is a really nice piece of starting with a tool (covalent peptides) and working to generate drug like molecules with favorable properties. 


Dr. Teddy Z said...

I do it all for you Pete.

Dan Erlanson said...

I wouldn't go so far as to call these "drug like molecules with favorable properties" given the guanidine, the 10 hydrogen bond donors, and the multiple rotatable bonds.

Also, just to be clear, the structure portrayed contains a thiazolidinedione, not a rhodnanine, though the two are similar. On that note, as the corresponding author himself warned in a previous publication, "we suggest that particularly strong requirements, i.e., affinity in the lower nanomolar range and proven selectivity for the target, are applied in the further assessment of rhodanines and related compounds."

Anonymous said...

Uh, Dudes... that's not a Rhodanine. A Rhodanine has a thiocarbonyl. The des-Sulfur version doesn't have the same real/perceived liabilities as a real rhodamine. Just check the available PAINS filters.

Dr. Teddy Z said...

Yes, the cap is a thiazolidinedione. I fall on my sword for sloppy writing done in a rush. The point I was trying to make is that they understood the liability of rhodanines in their caps fully, while many times people don't.

@Dan...I didn't mean to say these have drug like properties, but that they are working "to generate drug like molecules with favorable properties"...the key here being working towards.