Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing <sc>l</sc>-Thyroxine-Derived Prodrugs

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A90127%2F23%3A00139046" target="_blank" >RIV/00216224:90127/23:00139046 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01026" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01026</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.3c01026" target="_blank" >10.1021/acs.jmedchem.3c01026</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing <sc>l</sc>-Thyroxine-Derived Prodrugs

Popis výsledku v původním jazyce

OATP1C1 (organic anion-transporting polypeptide 1C1) transports thyroid hormones, particularly thyroxine (T4), into human astrocytes. In this study, we investigated the potential of utilizing OATP1C1 to improve the delivery of anti-inflammatory drugs into glial cells. We designed and synthesized eight novel prodrugs by incorporating T-4 and 3,5-diiodo-l-tyrosine (DIT) as promoieties to selected anti-inflammatory drugs. The prodrug uptake in OATP1C1-expressing human U-87MG glioma cells demonstrated higher accumulation with T-4 promoiety compared to those with DIT promoiety or the parent drugs themselves. In silico models of OATP1C1 suggested dynamic binding for the prodrugs, wherein the pose changed from vertical to horizontal. The predicted binding energies correlated with the transport profiles, with T-4 derivatives exhibiting higher binding energies when compared to prodrugs with a DIT promoiety. Interestingly, the prodrugs also showed utilization of oatp1a4/1a5/1a6 in mouse primary astrocytes, which was further supported by docking studies and a great potential for improved brain drug delivery.

Název v anglickém jazyce

Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing <sc>l</sc>-Thyroxine-Derived Prodrugs

Popis výsledku anglicky

OATP1C1 (organic anion-transporting polypeptide 1C1) transports thyroid hormones, particularly thyroxine (T4), into human astrocytes. In this study, we investigated the potential of utilizing OATP1C1 to improve the delivery of anti-inflammatory drugs into glial cells. We designed and synthesized eight novel prodrugs by incorporating T-4 and 3,5-diiodo-l-tyrosine (DIT) as promoieties to selected anti-inflammatory drugs. The prodrug uptake in OATP1C1-expressing human U-87MG glioma cells demonstrated higher accumulation with T-4 promoiety compared to those with DIT promoiety or the parent drugs themselves. In silico models of OATP1C1 suggested dynamic binding for the prodrugs, wherein the pose changed from vertical to horizontal. The predicted binding energies correlated with the transport profiles, with T-4 derivatives exhibiting higher binding energies when compared to prodrugs with a DIT promoiety. Interestingly, the prodrugs also showed utilization of oatp1a4/1a5/1a6 in mouse primary astrocytes, which was further supported by docking studies and a great potential for improved brain drug delivery.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30400 - Medical biotechnology

Projekt

—

Návaznosti

—

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Svazek periodika

66

Číslo periodika v rámci svazku

22

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

21

Strana od-do

15094-15114

Kód UT WoS článku

001142966000001

EID výsledku v databázi Scopus

2-s2.0-85178194269