During our screening of fermentation broths, culture UC 11136 was identified as producing potent inhibitor(s) of the in vitro cholesteryl ester transfer protein (CETP) reaction. Subsequent chemical isolation work identified two inhibitors of CETP produced by this culture. One of these inhibitors, U-106305, represented a novel CETP inhibitor as well as a structural class of compounds not previously reported from microbial fermentations. The structure of U-106305 was elucidated as V-isobutyl-tii(-rrtins-4,5:6,7:8,9:10,ll:12,13:16,17-hexamethylene-(£,£)-2,14-octadecadienamide by extensive NMR studies. Biogenetically, the backbone of U-106305 was found to derive from nine acetates linked in a head-to-tail fashion, while the cyclopropyl methylene carbons were derived from the methyl group of L-methionine. A biosynthetic pathway is proposed based on these findings.

The binding of two 5-substituted-l,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (Pl-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-I55 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzymehnhibitor complexes, the S 1 ' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.

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