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2 results on '"STABLE ANALOGS"'

1. Novel stable PACAP analogs with potent activity towards the PAC1 receptor

Author

Bourgault, Steve, Vaudry, David, Botia, Béatrice, Couvineau, Alain, Laburthe, Marc, Vaudry, Hubert, and Fournier, Alain

Subjects
*PROTEOLYTIC enzymes, *BLOOD coagulation factors, *COLLAGENASES, *PEPTIDASE
Abstract

Abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38- or 27-amino acid neuropeptide with promising therapeutic applications for the treatment of several pathophysiological states related to neurodegenerative diseases. However, its use for therapeutic applications is actually limited by its restricted bioavailability and rapid degradation. Therefore, metabolically stable PACAP analogs represent promising tools to further investigate the physiological roles of PACAP and ascertain its usefulness in some clinical conditions. In this study, derivatives of PACAP27 and PACAP38 have been rationally designed to develop PAC1 receptor agonists resistant to peptidase action. Results showed that N-terminal modifications confer resistance to dipeptidyl peptidase IV, a major proteolytic process involved in PACAP degradation. Moreover, in vitro incubation of both PACAP isoforms in human plasma revealed that PACAP38 is rapidly metabolized, with a half-life of less than 5min, while PACAP27 was stable in these experimental conditions. Hence, following the elucidation of its plasmatic metabolites, PACAP38 was modified at its putative endopeptidase and carboxypeptidase sites of cleavage. All peptide analogs were tested for their ability to bind the PAC1 receptor, as well as for their potency to induce calcium mobilization and inhibit PC12 cell proliferation through the PAC1 receptor. This approach revealed two leading compounds, i.e. acetyl-[Ala15, Ala20]PACAP38-propylamide and acetyl-PACAP27-propylamide, which exhibited improved metabolic stability and potent biological activity. This study describes innovative data related to PACAP metabolism in human plasma and depicts the development of a metabolically stable PACAP38 analog, acetyl-[Ala15, Ala20]PACAP38-propylamide, which behaves as a super-agonist towards the PAC1 receptor. [Copyright &y& Elsevier]

Published
2008
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2. 15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation

Author

Dianne Cooper, Niloufar Moradi-Bidhendi, Mark J. Paul-Clark, Derek W. Gilroy, and Thong van Cao

Subjects
Male, NF-KAPPA-B, nonsteroidal antiinflammatory drugs, Nitric Oxide Synthase Type II, CARRAGEENAN-INDUCED PLEURISY, Pharmacology, Research & Experimental Medicine, DEFICIENT MICE, chemistry.chemical_compound, Mice, Enos, Mechanism of action of aspirin, Leukocytes, Immunology and Allergy, ENDOTHELIAL CELL-ADHESION, Mice, Knockout, Aspirin, biology, LIPOXIN A(4), Anti-Inflammatory Agents, Non-Steroidal, Nitric Oxide Synthase Type III, 11 Medical And Health Sciences, Nitric oxide synthase, Lipoxins, STABLE ANALOGS, Medicine, Research & Experimental, medicine.symptom, Life Sciences & Biomedicine, Intravital microscopy, medicine.drug, Immunology, LEUKOCYTE ADHESION, Inflammation, Peritonitis, Nitric Oxide, Article, Nitric oxide, NO-RELEASING ASPIRIN, medicine, Animals, Endothelium, Rats, Wistar, Nitrites, leukocyte trafficking, Science & Technology, Dose-Response Relationship, Drug, business.industry, Microcirculation, resolution, biology.organism_classification, Rats, Mice, Inbred C57BL, chemistry, epi-lipoxins, biology.protein, microvascular endothelium, Nitric Oxide Synthase, business, PROSTAGLANDIN-H SYNTHASE, Interleukin-1
Abstract

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1β–induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1β–stimulated mouse mesentery. Not only did aspirin inhibit leukocyte–endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A4 had markedly reduced effects on leukocyte–endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A4, which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte–endothelium interactions.

Published
2004

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