Functional group replacement strategy

A strategy based on functional group replacement was developed to dissect the contribution of individual hydroxyl groups to the free energy... 

Initially, the Boc group was used for reversible a-amine protection and most side-chain functional groups were protected as benzyl derivatives, which are stable to Boc removal in HC1 or TFA. This Boc/Bzl strategy is still frequently used and is the method of choice in several laboratories. It has, however, been replaced in many laboratories by the base-labile Fmoc group, which allows weak acid deprotection of tert-butyl groups from the side chains. For short- and moderate-sized peptides both systems are effective. For protein synthesis, the relative merits have not yet been fully established. 

A new strategy for the design of semi-synthetic proteins and enzymes bearing non-natural functional groups involves the replacement of the native cofactors by modified cofactors chemically linked to functional groups providing novel properties. This approach allows the placement of artificial groups at specific positions in close vicinity to the cofactor site [237]. The incorporation of photosensitizer ... 

Scheme 19.25 Molecular design strategies leading to a representative HIV-1 Protease Inhibitor drug, namely saquinavir 91. LE = Lead enhancement where synthesis of numerous analogs eventually led to the next depicted molecule. Note replacement of an Initial peptidic linkage with a hydroxyl-ethylene blolsoster. The latter has also become a key functional group In many of the other newer HIV-1 Protease inhibitors. (With permission from Proudfoot.)...

---