Haptenic inhibitor

A comparative study of the carbohydrate-binding specificity of four 2-acetamido-2-deoxy-D-galactose-binding lectins (from Dolichos biflorus, Glycine max, Helix pomatia, and Phaseolus lunatus) has been conducted by using a series of model macromolecules for direct precipitation and a variety of mono- and oligo-saccharides as hapten inhibitors.592 The data indicated that the combining site of all four lectins... 

Basomba A, Pelaez A, Villalmanzo IG, Campos A (1978) Allergy to penicillin unsuccessfully treated with a haptenic inhibitor (Benzylpenicilloyl-N-formyllysine BPO-Flys). A case report. Clin Allergy 8 341... 

De Week AL, Jeunet F, Schulz KH, Louis P, Girard JP, Grilliat JP, Moneret-Vautrin D et al. (1975) Clinical trial of Ro 6-0787 a monovalent specific hapten inhibitor of penicillin allergy. Z. Immunitatsforsch 150 138... 

Levine BB (1960 c) Formation of D-penicillamine-cysteine mixed disulphide by reaction of D-benzylpenicilloic acide with cysteine Nature 187 940 Levine BB (1961) Studies on the formation of the penicillin antigen. II. Some reactions of D-benzylpenicillenic acid in aqueous solution at pH 7.5. Arch Biochem Biophys 93 50 Levine BB (1962) N(a-D-penicilloyfamines as univalent hapten inhibitors of antibody-de-pendent allergic reactions to penicillin. J Med Chem 5 1025 Levine BB (1963) Studies on the dimensions of the rabbit anti-benzyl penicilloyl antibody combining sites. J Exp Med 117 161... 

Antibody 15C5 was able to catalyse the hydrolysis of the triester [105] with cat 2.65 x 10 3 min 1 whilst a second antibody from the same immunization programme was later found to hydrolyse the acetylcholinesterase inhibitor Paraoxon [106] with kcat = 1.95 x 10 3min-1 at 25°C (Appendix entry 6.2) (Lavey and Janda, 1996b). Antibody 3H5 showed Michaelis-Menten kinetics and was strongly inhibited by the hapten [104]. It exhibited a linear dependence of the rate of hydrolysis on hydroxide ion concentration, suggesting that 3H5 effects catalysis by transition state stabilization rather than by general acid/base catalysis. 

Finally, the whole process of reactive immunization opens up the opportunity of using mechanism-based inhibitors as haptens, capable of actively promoting a desired mechanism by contrast to their conventional use as irreversible enzyme inhibitors. 

Figure 22 Penam sulfone 39, a mechanism-based inhibitor of /3-lactamase, used as a hapten to generate scFv antibodies, FT6 and FT12, with a /3-lactamase activity.

The latter approach has been followed in our laboratory. For instance, in studies related to the synthesis of potent multivalent sialoside inhibitors of influenza virus hemagglutinin [34], it became of interest to evaluate the immunogenicity of neoglycoproteins containing sialosides as sole immunodominant hapten. To this end, acetochloroneuraminic acid (1) was transformed into allyl glycoside 2 (Scheme 1) which upon reductive ozonolysis afforded aldehyde 3 in excellent overall yields [35], Reductive amination of 3 to bovine serum albumin (BSA) and tetanus toxoid provided immunogenic vaccines from which specific rabbit IgG anti-sialic acid antibodies were obtained [36]. In order... 

Phosphonates have been widely used as analogues of carboxylic acids. They have been particularly effective as analogues of tetrahedral transition states that occur in the course of enzyme-catalyzed reactions such as hydrolysis of the amide (peptide) bond. As such, they may be used as inhibitors of enzymes (e.g., 82, 83) or as haptens for producing antibodies that are catalytic (e.g., 84). A notable example is H203P— CH2—CH2—CH(—NH2)—COOH, which has effects that are likely to be due to its interference with glutamate as a neurotransmitter (85). 

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