Chemical Selection for Catalysis in Combinatorial Antibody Libraries

Abstract

For the past decade the immune system has been exploited as a rich source of de novo catalysts. Catalytic antibodies have been shown to have chemoselectivity, enantioselectivity, large rate accelerations, and even an ability to reroute chemical reactions. In many instances catalysts have been made for reactions for which there are no known natural or man-made enzymes. Yet, the full power of this combinatorial system can only be exploited if there was a system that allows for the direct selection of a particular function. A method that allows for the direct chemical selection for catalysis from antibody libraries was so devised, whereby the positive aspects of hybridoma technology were preserved and re-formatted in the filamentous phage system to allow direct selection of catalysis. This methodology is based on a purely chemical selection process, making it more general than biologically based selection systems because it is not limited to reaction products that perturb cellular machinery.

A Specific Activity‐Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease

“…[17,18] In addition, a few ABPs that enable non-reversible mechanism-based labeling of retaining β-galactosidases have been reported. These include suicide substrates bearing a latent quinone methide precursor as the aglycon to which a fluorescent or fluorogenic tag is attached [19][20][21][22] and 2-fluorogalactoside inhibitors in which the hydroxyl group at C6 is substituted with an azide, which enables two-step labeling via Staudinger-Bertozzi ligation. [23] To date, none of these probes has been used for the labeling of human retaining β-galactosidases.…”

Natural Catalytic Antibodies in Norm and in HIV-Infected Patients

“…Some studies describing these approaches include (Keinan, 2005, and refs therein). The employment of the approaches have demonstrated that the substrate specificity (and/or the specific activity) of some artificial Abzs is comparable to or even higher than that of enzymes with the same catalytic activity (Barbas et al, 1997;Janda et al, 1997;Keinan, 2005, and refs therein).…”

“…Mechanistic basis for the activity of such Abzs is becoming well understood (Janda et al, 1997;Thayer et al, 1999;Keinan, 2005, and refs therein). The field of artificial Abzs has been amply reviewed recently (Martin & Schultz, 1999;Suzuki, 1994;Keinan, 2005, and refs therein), for more detailed description of the relevant reactions.…”

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

“…124 I-TrapG can be converted by bG to form the quinine methide derivative of 124 I-Trap to quickly react with any nearby nucleophile moiety such as membrane proteins (23) (Fig. 1B).…”