RIFAMYCINS AS INHIBITORS OF COLLAGENASE ACTIVITY - THEIR POSSIBLE PHARMACOLOGICAL ROLE IN COLLAGEN DEGRADATIVE DISEASES

The interaction of commercial rifamycin SV, rifamycin B, rifampicin an d some other semi-synthetic analogous with collagenase in vitro was st udied by using the fluorogenic substrate Mca-Pro-Leu-Gly-Leu-Dpa-ALa-A rg-NH2. Increased fluorescence, due to the removal of the NH2-terminal dinitrophenyl group, after cleavage of the probe by collagenase was m onitored and related to the enzyme activity. The peptide was an effici ent substrate for collagenase with a K-m of 0.83 mu M at 20 degrees C in the presence of 10 mu M Ca2+, pH = 7.5. In the same conditions, in the presence of rifamycin SV, rifampicin and rifamycin B or their semi -synthetic analogues AM(41), MC(11) and MC(30), a marked inhibition of the enzyme activity was observed and an IC50 ranging from 13.1 to 20. 7 mu M was calculated. The inhibitory effect was reversible as demonst rated by restoration of enzyme activity by dialysis. These results may support the hypothesis that drugs based upon inhibitors of collagenas e activity will provide a therapeutical tool for the underlying pathol ogical destruction of extracellular matrix observed for instance in rh eumatoid arthritis as reported by several authors.