Prodrug activation via catalytic antibodies.
Prodrug activation via antibodies was examined by using the antibiotic chloramphenicol as a model drug. Based on the conformational change between substrate and product, this antibody-catalyzed reaction was designed to prevent product inhibition, thus enhancing turnover. Antibodies elicited against a phosphonate transition-state analogue were found to catalyze hydrolysis of a nonbioactive chloramphenicol monoester as a prodrug at a significantly higher rate above the uncatalyzed background reaction to regenerate chloramphenicol as a parent molecule. The antibody-catalyzed prodrug activation was tested by the paper-disc diffusion method using Bacillus subtilis as an indicator strain. The antibody 6D9 catalyzes the reaction with multiple turnover to generate enough chloramphenicol to inhibit bacterial growth, as indicated by a clear inhibitory zone after incubation with monoester. Using the same method, no inhibition was detected by incubation of either the monoester or the antibody alone. This result reveals that only the antibody hydrolytically activates the monoester, which can be expected to be a suitable prodrug, as it is resistant to the action of bacterial hydrolytic enzymes. The approach in this study demonstrates the use of catalytic antibody technology in medicine and may be applicable to drugs with undesirable effects, particularly in the field of cancer therapy.
Protein Engineering Research Institute, Osaka, Japan.
H
H
Miyashita
Y
Y
Karaki
M
M
Kikuchi
I
I
Fujii
D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001711:Biotransformation; D002384:Catalysis; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011355:Prodrugs / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D011355:Prodrugs; D002701:Chloramphenicol