It sounds like you may be working on a viral protease. If you can identify the site of polyprotein cleavage, you may be able to make an oligopeptide substrate labeled with fluorescence resonance energy transfer (FRET) donor and acceptor on opposite sides of the cleavage site. Using the purified protease and the FRET substrate, you can set up a continuous fluorescence-based in vitro assay to measure the potency and time-dependence of inhibitors.

Agree:  FRET is a good in-solution method. 

You may also want to try building ELISA-like assays, if you have antibodies to a few of the epitopes of the intact (starting) polyprotein.  The intact polyprotein could be captured by one antibody and 'detected' with another antibody.  But cleavage of the polyprotein should result in physically separating epitopes, detected as capture onto the first antibody but no detectable second epitope.  Simple before/after ELISA reactions could show the data you want.  If you have enough antibodies, you might be able to easily map cleavage effects along the polyprotein.

Another alternative:  if the polyprotein is relatively well purified, you might just be able to run sample on intact-protein mass spec.  It should be almost trivial to see mass changes that would result from cleavage.  But such mass spec tech is not necessarily trivial to operate, so finding a knowledgeable collaborator would be critical. 

You could also use SDS-PAGE to look for polyprotein processing.