title: An approach to sequence-specific antibody proteases. The use of haptens mimicking both a transition state and a distorted ground state.
abstract: We describe here a novel strategy for the isolation of antibodies with sequence-specific protease activity: the synthesis of dipeptide haptens in which the targeted peptide bond has been replaced by a ring-strained or torsionally strained hydroxyethylene transition-state analog. Thus, the analogs mimic both a peptide bond in a distorted, reactive conformation and the transition state for peptide bond hydrolysis. In order to obtain sequence-specific antibody proteases, these analogs have been flanked with additional amino acid residues in preparation for immunization. In particular, we have synthesized peptides containing analogs such as 2-cis-amino-3-cis-hydroxycyclobutane carboxylic acid and endo-(3-amino-2-hydroxy)bicyclo[2.2.1]-heptane-7-anti-carboxylic acid. We have also prepared a series of peptide derivatives containing analogs, such as 2-[3-amino-2-oxo-1-azetidinyl]-3-methylbutanoic acid, in which the targeted peptide bond has been incorporated into a beta-lactam ring. Since the "peptide bond" has been left intact, these species mimic only a distorted ground state. At present, antibodies are being elicited against a number of the above peptide derivatives.
authors.affiliation: Department of Chemistry, Amherst College, MA 01002.
authors.forename: R M
authors.initials: RM
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Yuan
authors.forename: D P
authors.initials: DP
authors.lastname: Weiner
authors.forename: C R
authors.initials: CR
authors.lastname: Dutton
authors.forename: D E
authors.initials: DE
authors.lastname: Hansen
mesh_terms: D017151:Antibodies, Catalytic / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D000918:Antibody Specificity; D010450:Endopeptidases / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D005030:Ethylenes / Q000737:chemistry; D006241:Haptens / Q000276:immunology; D006868:Hydrolysis; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D017151:Antibodies, Catalytic; D005030:Ethylenes; D006241:Haptens; D010455:Peptides; C067254:hydroxyethylene; D010450:Endopeptidases