Phosphorodithioates: synthesis and evaluation of new haptens for the generation of antibody acyl transferases

An extension of the transition state analogue (TSA) hapten approach for the elicitation of catalytic antibodies for acyl-transfer reactions is describ ed. It is based on the enlistment of phosphorodithioate 1 as a stable mimic of the putative tetrahedral intermediate (TI-) formed during the base-cata lyzed hydrolysis of bisaryl carbonate 2. Six members of a library of 25 mon oclonal antibodies elicited to 1 catalyze the hydrolysis of 2. The most eff icient catalyst, 48F10, exhibits Michaelis-Menten kinetics [K-m(2)=686 mu M , k(cat)(2)=2.7 min(-1), k(cat)(2)/k(uncat)(2)=3 x 10(4)] and is one of the most active carbonate hydrolyzing antibodies yet reported. This report hig hlights the utility of haptens that incorporate substitution of the non-bri dging phosphorus(V) oxygen atoms present in the more classical TSA approach es with sulfur, to elicit efficient catalysts for acyl-transfer processes. (C) 1999 Elsevier Science Ltd. All rights reserved.