From a filamentous phage library displaying random hexapeptides, we se
lected clones displaying peptides that bind S-protein, a 104-amino-aci
d (aa) fragment of bovine pancreatic ribonuclease (RNase). The selecte
d peptides show a sequence motif, (F/Y)NF(E/V)(I/V)(L/V), that bears l
ittle resemblance to S-peptide, a 20-aa fragment of RNase that is S-pr
otein's natural ligand. One of the displayed peptides, YNFEVL, was syn
thesized chemically and shown by isothermal titration calorimetry to b
ind S-protein with a dissociation equilibrium constant of 5.5 muM at 2
5-degrees-C, an affinity comparable to that of previously studied S-pe
ptide variants. The YNFEVL peptide is an antagonist of S-peptide, in t
hat it blocks the ability of S-peptide to restore enzyme activity to S
-protein. The S-protein/S-peptide system preserves the essential featu
res of a pharmacologically significant receptor/hormone couple, and th
e S-peptide antagonist can therefore be regarded as a new RNase-specif
ic 'drug'. This work illustrates the potential value of phage display
libraries for discovering novel classes of pharmaceuticals.