Catalytic antibody transition state analogs

Figure 3.2 Transition state analog principle for the design of catalytic antibodies.

Basmadjian G., Singh S., Sastrodjojo B. et al. Generation of polyclonal catalytic antibodies against cocaine using transition state analogs of cocaine conjugated to diphtheria toxoid. Chem. Pharm. Bull. 43 1902, 1995. 

Keywords Catalysis a Enzyme a Transition State Analog a RNA Catalysis a DNA catalysis a Catalytic Antibodies... 

The transition state analog (TSA) approach1651 which has proved so successful in the design of enzyme inhibitors and catalytic antibodies lends itself nicely, at least in principle, to the molecular imprinting of polymers. Polymerization carried out in the presence of the TSA, or with the TSA covalently but readily reversibly bound to a monomer, produces a polymer with a number of embedded TSA molecules. If these can be removed under rea-... 

M. M. Mader, P. A. Bartlett, Binding Energy and Catalysis The Implications for Transition-State Analogs and Catalytic Antibodies , Chem. Rev. 1997, 97,1281-1301. 

Designing haptens in order to stimulate the production of catalytic antibodies depends on a variety of strategies based on transition state analogs, entropy traps and opportunistic chemistry. 

Using the transition-state analog shown on p. 485 a catalytic antibody with chorismate mutase activity was isolated. Many antibodies catalyzing additional reactions have also been found. Although they are usually less active than natural enzymes, in some cases they approach enzymatic rates. Furthermore, they may catalyze reactions for which no known enzymes exist.h... 

The idea that antibodies raised against transition-state analogs should show specific catalytic activity is beautiful and seductive. In the tenth year since the idea became an experimental reality, a preliminary assessment of their potential was made (Kirby, 1996). It was concluded that their high stereoselectivity makes abzymes excellent prospects for asymmetric synthesis, though their practical usefulness is currently limited by their catalytic efficiency. 

Baca, M., Scanlan, T. S., Stephenson, R. C., and Wells, J. A. (1997). Phage display of a catalytic antibody to optimize affinity for transition-state analog binding. Proc. Natl. Acad. Sci. USA, 94(19), 10063-10068. 

Scheme 4.12 Catalytic antibody 1F7 was raised against the transition state analog 28 and possesses modest chorismate mutase activity. It can complement a permissive yeast strain that is auxotrophic for phenylalanine and tyrosine by replacingthe natural enzyme (CM) in the shikimate biosynthetic pathway.

The first anti-cocaine catalytic antibody was reported by Landry and associates in 1993 [22]. The transition-state analog used to ehdt the first anticocaine catalytic antibody was a stable structure of the transition state for the benzoyl ester hydrolysis of chair cocaine [22,25]. Based on the computational analysis discussed above, the new TSA structure depicted in Fig. 4 was synthesized and 85 cocaine esterases out of 450 anti-analog antibodies... 

This direct comparison of hapten design approaches for the same reaction revealed that antibodies generated by each method exhibit quite different catalytic behavior. The transition state analog approach provided catalytic antibodies with good turnover numbers and enanatiomeric discrimination however, it suffered from varying degrees of product inhibition by phenol 13. Comparatively, the reactive immunization approach yielded antibodies that are ultimately better catalysts because, once an... 

---