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MODULIRANJE IMUNOLOŠKOG ODGOVORA BIOAKTIVNIM PEPTIDIMA



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MODULIRANJE IMUNOLOŠKOG ODGOVORA BIOAKTIVNIM PEPTIDIMA

MODULATION OF IMMUNOLOGICAL RESPONSE BY BIOACTIVE PEPTIDES
Voditeljica projekta: dr. sc. Biserka Pokrić

Tel. ++385 1 4680 193   e-mail: pokric@irb.hr



Suradnici
Biserka Pokrić, doktorica kem. znanosti, znanstvena savjetnica
Nikola Štambuk, doktor med. znanosti, viši znanstveni suradnik

Program rada i rezultati na projektu:

Teorija molekularnog prepoznavanja zasniva se na činjenici da peptidi definirani komplementarnim RNA pokazuju visok afinitet vezivanja. Teorija je ispitana s obzirom na interakciju sens-antisens peptida, te hidropatija komplementarnih parova amino kiselina prisutnih u 10 peptidnih ligand-receptor sustava. Prikazan je postupak za optimizaciju broja mogućih komplementarnih parova. Teorijski koncept provjeren je in vivo za alfa-hormon koji stimulira melanocite (alfa-MSH) te njegov komplementarni peptid, na standardnom modelu citoprotekcije želučane sluznice u štakora. Zaključeno je kako metode teorije molekularnog prepoznavanja predstavljaju koristan postupak koji omogućuje pojednostavljenje eksperimenta, redukciju troškova peptidne sinteze i pojednostavljenje modeliranja peptida.

Ispitani su učinci neuropeptida met-encefalina na bronhokonstrikciju izazvanu histaminom u eksperimentalnom modelu astme. Mjerenja su ukazala da je modulatorni učinak met-encefalina na ovisan o dozi. Dodatne studije potrebne su kako bi se definirali mogući terapijski učinci met-enkefalina u respiratornoj farmakologiji.

Kvantifikaciran je in vivo učinak alfa-MSH na štakorskom modelu upalne bolesti crijeva inducirane s 2,4,6-trinitrosulfonbenzenskom kiselinom (TNBS). Struktura alfa-MSH analizirana je uporabom NMR spektroskopije. Površina oštećenog debelog crijeva statistički je značajno smanjena kod pretretmana s jednom dozom 1 mg/kg alfa-MSH, u odnosu na kontrolne životinje (p = 0.0147). Više i niže doze nisu imale značajne učinke. Pojedinačna doza od 1 mg/kg alfa-MSH uzrokovala je statistički značajnu i farmakološki relevantnu citoprotekciju. Rezultati ukazuju na učinkovitost alfa-MSH peptida u kontroliranju upale i upućuju na potrebu daljnjih in vitro i in vivo istraživanja kako bi se procijenio značaj i učinkovitost alfa-MSH u kontroli upalne bolesti crijeva. NMR mjerenja u vodenoj otopini podupiru pretpostavku o konformaciji alfa-MSH i njegove konzervirane sekvence u obliku ukosnice.

Ispitivana je učinkovitost monoterapije latanoprostom (Xalatan™) u primarnom glaukomu otvorenog kuta. Latanoprost je prostagladinski analog, čisti 15(R) epimer 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α-isopropyl estera. Latanoprost se aktivira enzimskom hidrolizom u rožnici, pri čemu postaje aktivan. Lijek snižava očni tlak povećavajući uveo-skleralno otjecanje. U studiji je utvrđena superiornost monoterapije latanoprostom u odnosu na druge kombinacije antiglaukomatoznih lijekova zbog zadovoljavajuće kontrole očnog tlaka i vrlo dobre prihvatljivosti. Na osnovu prosječne redukcije intraokularnog tlaka izmjerene na kraju praćenja (dan 60), zaključeno je da uporaba latanoprosta omogućuje bolju kontrolu intraokularnog tlaka uz manje nuzpojava i moguću redukciju troškova daljnjeg liječenja.

Research programme and results:

Molecular Recognition Theory is based on the finding that peptides specified by the complementary RNAs bind to each other with higher specificity and efficacy. This theory is investigated considering the interaction of the sense peptides coded by means of messenger RNA (read in 5' -3' direction) and antisense peptides coded in 3' -5' direction. The hydropathy of the complementary amino acid pairs and their frequencies in 10 peptide-receptor systems with verified ligand-receptor interaction was analyzed. An optimization procedure aimed to reduce the number of possible antisense peptides derived from the sense peptide has been proposed. Molecular Recognition Theory was also validated by an "in vivo" experiment. It was shown that 3' -5' peptide antisense of alpha-MSH abolished its cytoprotective effects on the gastric mucosa in rats. Molecular Recognition Theory could be useful method to simplify experimental procedures, reduce the costs of the peptide synthesis, and improve peptide structure modelling.

The effects of the neuropeptide met-enkephalin on histamine-induced bronhoconstriction in an experimental model of asthma was studied. The results implicate a dose-related modulatory effect of met-enkephalin on the bronchoconstrictor action of histamine. The studies, required to define practical and therapeutical use of the presented observations in respiratory pharmacology, are continued.

The dose-dependent "in vivo" effect of alpha-melanocyte stimulating hormone (alpha-MSH) in a rat model of inflammatory bowel disease induced by 2,4,6-tri nitrobenzene sulphonic acid (TNBS) was investigated. Alpha-MSH structure was analyzed by means of NMR spectroscopy. The area of colonic darnage was significantly reduced following pretreatment with a single dose of 1 mg/kg alpha-MSH, as compared to control animals. (p = 0.0147). Higher and lower doses had no significant effects. The results point to alpha-MSH effectiveness in controlling inflarnmation and imply that further "in vitro" and "in vivo" experiments should be carried out to judge the importance and relevance of alpha MSH in the control of inflammatory bowel disease. NMR data support a hairpin loop conformation of alpha MSH in water solution, which includes conserved message sequence.

The effectiveness of latanoprost (Xalatan TM) monotherapy in primary open angle glaucoma (POAG) was evaluated. Latanoprost is a prostaglandin analogue, the pure 15(R) epimer of 13,14 dihydro 17 phenyl 18,19,20 trinor PGF2alpha isopropyl ester. As a prodrug it is being activated by enzymatic hydrolysis in the cornea after which it becomes active acid of latanoprost. Latanoprost is lowering the intraocular pressure (IOP) by increasing the uveoscleral outflow. In this study, latanoprost was used once daily as monotherapy what offers much better compliance for the patients than other combinations of drugs, preserving good IOP control. Based on the significant reduction of the IOp, measured on the day 60 of the trial, it is concluded that use of latanoprost is advisable when calculating better IOP control, few side-effects and reductions in costs of potential surgical procedures.



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