Caspases have been strongly implicated to play an essential role in apoptosis. A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7. The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis. Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-Å resolution. In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S 2 subsite, and do not bind in the caspase primary aspartic acid binding pocket (S 1 ). These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes. Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.

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The EtOAc extract of the sponge Xestospongia muta collected in Colombus Island, Bahamas, yielded eleven straight-chain unsaturated, polyacetylenic, brominated acids, seven of which were identified on the basis of spectral data, including the unknown acids 2-7. These acetylenic acids are the first known examples that have been shown to inhibit HIV protease, a critical enzyme in the replication of human immunodeficiency virus.

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Nine triterpenes with antiviral activity against Herpes simplex virus types I and II in vitro were isolated from dammar resin. Each compound caused a significant reduction in viral cytopathic effect when Vero cells were exposed continuously to 1-10 micrograms/ml of compound for 48 h after viral challenge. The triterpenes were identified as dammaradienol [1], dammarenediol-II [2], hydroxydammarenone-I [3], ursonic acid [5], hydroxyhopanone [11], dammarenolic acid [15], shoreic acid [16], eichlerianic acid [17], and a novel compound, hydroxyoleanonic lactone [7], on the basis of their chromatographic, spectroscopic, and physical properties.