General Properties of Phosphinic Peptides

Another motivation to use phosphorus-containing peptides is related to their good structural analogy with what is called the substrate structure in the transition-state. As shown in Fig. 3, three possibilities can be envisaged and have been explored to develop potent inhibitors. Phosphonamide peptides seem the most obvious choice, as the analogy is almost perfect [11, 12]. If such compounds have been proved to yield potent inhibitors towards some zinc-metalloproteases, the limited stability of the P-N bond through hydrolysis has prevented further use of this chemistry [13-15]. Phosphonates have been reported to yield one of the most potent inhibitor ever reported for carboxypeptidase A (Ki in the fM range) [13]. However, when tested with endoproteases, phosphonates turned out to be less potent [15]. 

These remarks have historically justified the development of the chemistry of phosphinic peptides as stable compounds and the ability to inhibit zinc-proteases potently [16]. Indeed, it has been found that the replacement of an NH by a CH2 

---