The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPAR␣, PPAR␦, and PPAR␥. PPAR␥ has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPAR␥ and PPAR␦ that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPAR␥ and PPAR␦ directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPAR␥ agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPAR␥ agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and triglyceride concentrations. In contrast, selective in vivo activation of PPAR␦ did not significantly affect these parameters. In vivo PPAR␣ activation with WY-14653 resulted in reductions in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1) synthetic non-thiazolidinediones can serve as ligands of PPAR␥ and PPAR␦; 2) ligand-dependent activation of PPAR␦ involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding protein; 3) PPAR␥ activation (but not PPAR␦ or PPAR␣ activation) is sufficient to potentiate preadipocyte differentiation; 4) non-thiazolidinedione PPAR␥ agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPAR␣ activation is sufficient to affect triglyceride metabolism, PPAR␦ activation does not appear to modulate glucose or triglyceride levels.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARK K and PPARQ Q, relatively little is known about the most widely expressed PPAR subtype, PPARN N. Here we show that treatment of insulin resistant db/db mice with the PPARN N agonist L-165 041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165 041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARN N ligand, but was increased by a PPARQ Q agonist. These data suggest both that PPARN N is involved in the regulation of cholesterol metabolism in db/db mice and that PPARN N ligands could potentially have therapeutic value. z 2000 Federation of European Biochemical Societies.

22,23-Dihydroavermectin B1, ivermectin, derived from avermectin B1 by selective hydrogenation using Wilkinson's homogenous catalyst [Ph3P)3RhCl], was shown to be a highly effective drug for the treatment of a wide variety of metazoan parasitic diseases in animals.

9 -{[2 -Hydroxy-I -(hydroxymethyl)ethoxy]methyllguanine (2'-nor-2'-deoxyguanosine; 2'NDG) selectively inhibits the replication of herpes group viruses. In cell culture studies 2'NDG was at least 10-fold more potent than acyclovir (ACV) in inhibition of human cytomegalovirus replication and Epstein-Barr virus-induced lymphocyte transformation and was about as effective as ACV in inhibition of herpes simplex viruses 1 and 2 and varicella zoster virus. Orally administered 2'NDG was 6-to 50-fold more efficacious than ACV in treating systemic or local HSV-1 infection or HSV-2 intravaginal infection in mice. The mode of action of 2'NDG appears to involve phosphorylation by herpes simplex virus thymidine kinase and subsequent phosphorylations by cellular kinases to produce 2'NDG triphosphate, which is a potent inhibitor of herpes virus DNA polymerase. Compared to ACV, 2'NDG was a more efficient substrate for HSV-1 thymidine kinase (Vma./Km for 2'NDG 30-fold higher than that for ACV), whereas 2'NDG monophosphate is a more efficient substrate for GMP kinase (Vm./Km for 2'NDG monophosphate 492-fold higher than that for ACV monophosphate). The combined effect is more rapid production of the inhibitory triphosphate from 2'NDG than from ACV.As part of our studies on the structure-activity relationships of herpes virus encoded thymidine kinase (TK) and DNA polymerase, a nucleoside analog, 9-{[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl}guanine (2'-nor-2'-deoxyguanosine; 2'NDG) (1-3) was synthesized. 2'NDG is an efficient substrate for the herpes simplex virus 1 (HSV-1) TK and is readily converted to the triphosphate, a potent inhibitor of viral DNA polymerase (1).In the present studies, a chemical synthesis of 2'NDG, the characteristics of its selective phosphorylation by HSV-1 TK, and its rapid conversion to the triphosphate are more fully described. In addition, data are presented demonstrating that the rapid phosphorylation of 2'NDG is correlated with potent inhibition of herpes virus replication in cell cultures and both prophylactic and therapeutic efficacy against herpes virus infections in mice.MATERIALS AND METHODS Materials. Phosphocreatine, creatine kinase, ATP, deoxythymidine, and dGMP were purchased from Sigma; GMP kinase (hog brain) and NADH, from Boehringer Mannheim; lactate dehydrogenase, from Worthington; [methyl-3H] by determining the drug concentration (,ug/ml) required to confer a 50% plaque inhibition on duplicate cell monolayers [for HSV-1, VZV, HCMV, Mengo virus, and vaccinia virus]. For both assays, the antiviral compound was added to the maintenance medium at the time of infection. Viral cytopathic effect was evaluated after incubation for 5 days at 37°C, and plaque development was evaluated after incubation for 3 days (7 days for HCMV) at 370C. Inhibition of EBV replication was measured by prevention of transformation of normal cord lymphocytes to lymphoblastoid cells. In brief, lymphocyte-rich suspensions were prepared from fresh, heparinized human cord blood specimens by differential centrifu...

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