Pyroglutamyl diazomethyl ketone and N-benzyloxycarbonyl prolyl prolinal, specific inhibitors of pyroglutamyl peptidase I and prolyl endopeptidase respectively, were used to study the possible role of these enzymes in the regulation of thyrotropin releasing hormone turnover. In vitro thyrotropin releasing hormone release by male rat hypothalamic slices was studied. Combined in vitro treatment with 10(-5)M of both inhibitors totally inhibited both enzymatic activities. The treatment did not affect basal or 56 mM K+ induced thyrotropin releasing hormone release or thyrotropin releasing hormone levels in slices. Repeated combined intraperitoneal injections of the two inhibitors for up to 12 hours produced a 70%-95% reduction in mouse brain pyroglutamyl peptidase I specific activity and a 65%-85% reduction in prolyl endopeptidase specific activity. Thyrotropin releasing hormone levels were unaffected by this treatment in all regions tested. The data suggest that these two enzymes are not involved in the intra- or extracellular control of thyrotropin releasing hormone levels in brain or hypophysis.

Aminopeptidases↗

PubMedDate not supplied

Inhibition of human immunodeficiency virus type 1 infection in a T-cell line (CEM) by new dipeptidyl-peptidase IV (CD26) inhibitors.

Phenylalanyl-pyrrolidine-2 nitrile (Phe-pyrr-2-CN) and arginyl(PMC)-pyrrolidine-2-nitrile (Arg(PMC)-pyrr-2-CN) are two dipeptidyl peptidase IV/CD26 (DPP-IV/CD26) inhibitors designed and synthesized by our group. These two compounds suppress the enzymatic activity of DPP-IV/CD26 in a competitive and reversible manner. Pretreatment of CEM cells with either of the compounds yielded a marked albeit transient reduction of HIV infection, as measured by HIV1 p24 production, RT activity and syncytium formation. The ID50 value of the Phe-Pyrr-2-CN and Arg(PMC)-pyrr-2-CN in HIV1 inhibition was 5.3 microM and 2.4 microM, respectively. Administration of either of the DPP-IV/CD26 inhibitors 1 h after HIV1 infection did not suppress HIV1 production. An analog whose inhibitory activity toward DPP-IV/CD26 was abolished by blocking the N-terminal of Phe-pyrr-2-CN with the 9-fluorenymethyloxycarbonyl (Fmoc) group had no effect on HIV1 infection. An additive effect of HIV1 inhibition was observed in combinations of either of the DPP-IV/CD26 inhibitors with CD4 monoclonal antibody. These results suggest that DPP-IV/CD26 enzymatic activity may play a role in facilitating HIV1 infection of human CD4+T cells at the entry process. DPP-IV/CD26 inhibitors may therefore have potential use in combination with other drugs to prevent HIV1 transmission.

Anti-HIV Agents↗

PubMedDate not supplied

Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice.

The ubiquitin-proteasome pathway is becoming an attractive target in cancer therapy. The inhibitors of proteasomes have recently been shown to induce apoptosis of tumor cells in vitro and to exert significant antitumor effects in murine tumor models in vivo. Proteasome inhibitors, also prevent NF-kappa B activation. Since this transcription factor is responsible for counteracting apoptosis induced by numerous agents, and proteasome inhibitors have already proved efficacious in increasing the proapoptotic activity of TNF in vitro, we decided to evaluate the antitumor effects of the combined PSI and TNF treatment against a murine C-26 carcinoma. Both agents separately exerted moderate antitumor efficacy. However, their combination proved to exert dramatic antitumor activity with retardation of tumor growth and prolongation of mice survival time. Moreover, 50% of the mice were completely cured by this drug combination. Unexpectedly, there was no potentiation of the cytostatic/cytotoxic effects of these drugs in in vitro assays which argues against the direct influence on C-26 cells. Similarly, the influence of these drugs on tumor induced angiogenesis does not seem to explain the observed antitumor effects. Further studies are necessary to explain the striking antitumor effects of the PSI and TNF combination.

Acetylcysteine↗

PubMedDate not supplied

A study of spinal fluid homovanillic acid (HVA) in patients with diseases of the nervous system.

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Chorea↗

PubMedDate not supplied

Kidney as a site of uptake and metabolism of gamma-glutamyl compounds.

gamma-Glutamyl derivatives of amino acids are extensively metabolized and accumulated in the kidney. The kideny also has a high capacity to synthesize ophthalmic acid, an analog of glutathione. These processes can be attributed to the high activity in the kidney of enzymes that both degrade and synthesize glutathione. Th possibility of using the gamma-glutamyl group as a carrier for the introduction of compounds containing an amino function into kidney metabolism was explored. Administration of L-gamma-glutamyl-L-3,4-di-hydroxyphenylalanine (gamma-glutamyl-DOPA) to rats led to the accumulation of gamma-glutamyl-DOPA in the kidney, release of DOPA and its conversion to dopamine by the action of aromatic amino acid decarboxylase. Dopamine actively generated in the kidney increased renal plasma flow and sodium excretion. No systemic effects or untoward reactions attributable to this amine were observed. It is suggested that gamma-glutamyl derivatives of certain drugs may be useful as kidney specific prodrugs.

Amino Acids↗

PubMedDate not supplied

[Strategies for identification of secretases implicated in Alzheimer's disease].

In Alzheimer's disease, cortical areas of affected patients are invaded by extracellular proteinous deposits called senile plaques, the main component of which is called amyloid beta-peptide or A beta. This peptide derives from the proteolytic attack of a precursor, the beta-amyloid precursor protein, by two enzymes called beta- and gamma-secretases. Alternatively, beta APP can be cleaved by an additional activity named alpha-secretase that occurs inside the A beta sequence, thereby precluding its formation, and concomitantly liberating a secreted fragment, namely APP alpha. Therefore, secretases seem to play a key role in the control of physiological and potentially pathogenic beta APP catabolites and could be envisioned as possible therapeutic targets in Alzheimer's disease. Here, we describe possible experimental approaches to identify such proteolytic activities.

Alzheimer Disease↗