The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of approximately 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.

Betulinic acid [1] and platanic acid [2], isolated from the leaves of Syzigium claviforum, were found to be inhibitors of HIV replication in H9 lymphocyte cells. Evaluation of anti-HIV activity with eight derivatives of 1 revealed that dihydrobetulinic acid [3] was also a potent inhibitor of HIV replication. The C-3 hydroxy group and C-17 carboxylic acid group, as well as the C-19 substituents, contribute to enhanced anti-HIV activity. The inhibitory activity of these compounds against protein kinase C (PKC) was also examined, since a correlation between anti-HIV and anti-PKC activities has been suggested. However, there was no apparent correlation between anti-HIV activity and the inhibition of PKC among these compounds.

Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there might be a relationship between ER structure and activity. Different ER modulators may induce conformational changes in the receptor that result in a specific biological activity. To investigate the possibility of modulator-specific conformational changes, we have applied affinity selection of peptides to identify binding surfaces that are exposed on the apo-ERs ␣ and ␤ and on each receptor complexed with estradiol or 4-OH tamoxifen. These peptides are sensitive probes of receptor conformation. We show here that ER ligands, known to produce distinct biological effects, induce distinct conformational changes in the receptors, providing a strong correlation between ER conformation and biological activity. Furthermore, the ability of some of the peptides to discriminate between different ER ␣ and ER ␤ ligand complexes suggests that the biological effects of ER agonists and antagonists acting through these receptors are likely to be different.

A model for microsomal glucose 6-phosphatase (EC 3.1.3.9) is presented. Glucose 6-phosphatase is postulated to be resultant of the coupling of two components of the microsomal membrane: 1) a glucose 6-phosphate - specific transport system which functions to shuttle the sugar phosphate from the cytoplasm to the lumen of the endoplasmic reticulum; and 2) a catalytic component, glucose-6-P phosphohydrolase, bound to the luminal surface of the membrane. A large body of existing data was shown to be consistent with this hypothesis. In particular, the model reconciles well-documented differences in the kinetic properties of the enzyme of untreated and modified microsomal preparations. Characteristic responses of the enzyme to changes in nutritional and hormonal states may be attributed to adaptations which alter the relative capacities of the transport and catalytic components.