Lipid bilayer position and orientation of novel carprofens, modulators of gamma-secretase in Alzheimer's disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F18%3A73591642" target="_blank" >RIV/61989592:15310/18:73591642 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0005273618302670" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0005273618302670</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbamem.2018.09.003" target="_blank" >10.1016/j.bbamem.2018.09.003</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Lipid bilayer position and orientation of novel carprofens, modulators of gamma-secretase in Alzheimer's disease

Popis výsledku v původním jazyce

gamma-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-beta peptides. Amyloid-beta peptides are considered causative agents for Alzheimer&apos;s disease and drugs targeted at gamma-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed gamma-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to gamma-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner.

Název v anglickém jazyce

Lipid bilayer position and orientation of novel carprofens, modulators of gamma-secretase in Alzheimer's disease

Popis výsledku anglicky

gamma-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-beta peptides. Amyloid-beta peptides are considered causative agents for Alzheimer&apos;s disease and drugs targeted at gamma-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed gamma-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to gamma-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES

ISSN

0005-2736

e-ISSN

—

Svazek periodika

1860

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

10

Strana od-do

2224-2233

Kód UT WoS článku

000447557500008

EID výsledku v databázi Scopus

2-s2.0-85053162104