Transition inhibitors, multiple

Tian, G., Ghanekar, S.V., Aharony, D., et al. (2003) The mechanism of y-secretase. Multiple inhibitor binding sites for transition state analog and small molecule inhibitors. J. Biol. Chem., 278, 28968-28975. 

Sirolimus has pleotropic effects on a wide variety of cell types with relevance to restenosis. The underlying mechanism of action of the compound is as an inhibitor of the cell cycle, with its principal effect on the G I to S transition (40), Importantly, sirolimus affects the numerous cell types thought to be involved in the restenotic process including cells typically resident to the vascular wall, such as SMCs, as well as those recruited from the circulation at times of injury such as immune constituents, As the complete delineation of the steps and mechanisms of restenosis remain to be determined, the benefit of sirolimus may be due to its ability to affect the multiple cell types involved. 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

Multiple efforts have been made to replace phosphorous-containing linkages with sulfur-containing isosteres in the context of enzyme inhibition. In a search for nonionic transition state analog inhibitors of restriction enzymes, Blattler et al. (34) found that nucleic acid duplexes that incorporate a dimethyl sulfone in place of a phosphodiester have distorted backbones similar to those in restriction enzyme bound DNA. Chimeric DNAs that incorporate sulfone hnkages were synthesized, and depending on the location of the dimethylene sulfone hnker, either between the first AT unit or the second AT unit in the EcoRV recognition site, values were 20 nM and 120... 

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