The making of Darunavir

Arun Ghosh at Purdue has written a review (Ref. below) of his group's development of Darunavir, the novel bis-THF containing HIV protease inhibitors. For some reason, I find this work very nice, both for its rational nature, and for the novelty of the structures.

It's interesting that the work started from a simple premise; that inhibitors targeting the backbone atoms of the protease would be effective across many mutant strains, as the virus cannot really afford to change these residues without serious problems. As with other hypotheses, this was easier stated than proven, but the targeting of two backbone Asp residues in the protease through hydrogen bonding with the bis-THF turned out to be a neat and predictable strategy. Ample crystal structures confirmed this.

Some of the nibs show crazy IC50s (4 pM for one of them). Darunavir (16 pM) was approved by the FDA in 2006. As far as I can tell, the synthesis too looks simple and facile.

Really nice example of rational drug design in my opinion.

Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance
Arun K. Ghosh, Bruno D. Chapsal, Irene T. Weber, and Hiroaki Mitsuya
DOI: 10.1021/ar7001232