The six series of unique tetrapeptides and their blocked N-acetyl, C-amide, and N-acetyl-C-amide analogues which comprise the hinge region of human IgA1 (Ser224 to Ser240) have been synthesized and tested as inhibitors of the type 1 IgA1 proteinase elaborated by Neisseria gonorrhoeae (EC 3.4.24.13). Most series had at least one member with an IC50 value less than 1 mM. The most effective inhibitors came from the series Ser-Thr-Pro-Pro (P4-P1) and Pro-Thr-Pro-Ser (P1-P3'). One member from each series had an IC50 value in the low microM range. Magnetic resonance studies (Siemion, I. Z.; et al. Biophys. Chem. 1988, 31, 35) indicate that the various tetrapeptide series appear to have different preferred solution conformations. However, these do not appear to be correlated with affinity for the neisserial proteinase. The most effective inhibitors tend to have a threonine residue adjacent to the N-terminus and the P1 or P1' residues at either the N- or the C-terminus. These relationships are not exclusive however, as other inhibitors, which do not meet these criteria, bind reasonably well. The most effective substrate analogues outlined here are about one-half the size and bind to the neisserial proteinase 2 orders of magnitude more tightly than previously reported inhibitors.