Antibodies 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. 

More recently, antibodies have also been generated against the KLH conjugate of arylphosphonamide (a transition state analog). 

Lemer and Benkovic examined the possibility of performing an intramolecular cyclisation reaction [30]. They chose the formation of a six-membered lactone ring from a hydroxy ester (12) and observed that only one single enantiomer of the 5-lactone (14) in 94% ee was formed from the corresponding 5-hydroxy ester. Moreover, the stereospecific ring closure reaction was accelerated by the antibody -elicited from the transition-state analog 15- by about a factor of 170. 

A suitable stable transition state analog is hexachloronorbomene derivative 25, which mimics most of the geometrical features of the transition state, including the boat conformation of the cyclohexene ring. It was used to poduce antibodies that catalyse the reaction between 20 and 21 efficiently, with substantial rate acceleration and multiple turnovers. 

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. 

McCafferty, J., Fitzgerald, K. J., Eamshaw, J., Chiswell, D. J., Link, J., Smith, R., and Kenten, J. (1994) Selection and rapid purification of murine antibody fragments that bind a transition-state analog by phage-display. Appl. Biochem. Biotech. 47, 157-173. 

Amide hydrolysis is energetically more demanding than ester hydrolysis or transacylation, and its catalysis by antibodies represents a formidable challenge. Although phosphonamidates would appear to be excellent transition-state analogs, numerous attempts in many laboratories to use these compounds to produce... 

Pandit and co-workers adopted the same strategy to catalyze a hetero-Diels-Alder reaction in which an aryl-nitroso derivative serves as the dienophile.117 118 Antibodies generated against thebicyclic transition-state analogs 133 and 134 accelerated the reaction between the trans-diene 135 and 136, but the ratio of the two product regioisomers 137 and 138 was the same as for the uncatalyzed reaction (58 42). In experiments with stoichiometric amounts of trans-135 and antibody 309-1G7, derived from hapten 134, this ratio was altered somewhat in favor of product 138 (47 53), in accord with the structure of the... 

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. 

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