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|
|9. Phenyl-glycine hybrid|
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).