Inhibition of IgA1 proteinases from Neisseria gonorrhoeae and Hemophilus influenzae by peptide prolyl boronic acids.
The alpha-aminoboronic acid analog of proline has been synthesized and incorporated into a number of peptides as the COOH-terminal residue. These peptide prolyl boronic acids are potent inhibitors of both the type 1 and type 2 IgA proteinases from Neisseria gonorrhoeae and Hemophilus influenzae, but not of the functionally similar IgA proteinase from Streptococcus sanguis. The best inhibitors synthesized thus far have Ki values in the nanomolar range (4.0 to 60 nM). These results indicate that the N. gonorrhoeae and the H. influenzae enzymes belong to the serine protease family of proteolytic enzymes while that from S. sanguis does not. As a group, the IgA proteinases have been noted for their remarkable specificity; thus, the peptide prolyl boronic acids reported here are the first small synthetic molecules to exhibit a relatively high affinity for the active site of an IgA proteinase and are therefore the first to yield some insight into the active site structure and specificity requirements of these enzymes.
Bachovchin
W W
WW
Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111.
Plaut
A G
AG
Flentke
G R
GR
Lynch
M
M
Kettner
C A
CA
D000595:Amino Acid Sequence; D001665:Binding Sites; D001897:Boronic Acids / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000201:enzymology*; D007070:Immunoglobulin A; D007143:Immunoglobulin Heavy Chains; D008969:Molecular Sequence Data; D009344:Neisseria gonorrhoeae / Q000201:enzymology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D011392:Proline; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship
D001897:Boronic Acids; D007070:Immunoglobulin A; D007143:Immunoglobulin Heavy Chains; D010455:Peptides; D011392:Proline; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; C021433:IgA-specific serine endopeptidase