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Comparative analysis of new peptide conjugates of antitubercular drug candidates – model membrane and in vitro studies

Ábrahám, Ágnes and Baranyai, Zsuzsa and Gyulai, Gergő and Pári, Edit and Horváti, Kata and Bősze, Szilvia and Kiss, Éva (2016) Comparative analysis of new peptide conjugates of antitubercular drug candidates – model membrane and in vitro studies. COLLOIDS AND SURFACES B-BIOINTERFACES, 147. pp. 106-115. ISSN 0927-7765

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Abstract

Novel peptide conjugates of two antitubercular drug candidates were synthesised and characterised using new tuftsin peptide derivatives (OT14) as carrier moiety. As antitubercular drug candidates two pyridopyrimidine derivatives, TB803 (2-allylamino-4-oxopyrido[1,2-a]pyrimidine-3-carbaldehyde) and TB820 (4-oxo-2-(pyrrolidin-1-yl)-pyrido[1,2-a]pyrimidin-3-carbaldehyde) inhibiting vital enzyme of Mycobacterium tuberculosis were applied. Membrane affinity of the compounds TB803 and TB820 and their peptide conjugates was evaluated using experimental lipid mono- and bilayer models. Penetration ability was assessed tensiometrically from Langmuir monolayer study and applying quartz crystal microbalance for the supported lipid bilayer (SLB) system. Minimal inhibitory concentration (MIC) values remained in a similar micromolar range for both of the conjugates while their cellular uptake rate was improved significantly compared to the drug candidates. A correlation was found between membrane affinity properties and results of in vitro biological investigations. Analysis of physical/structural properties of SLB in contact with bioactive components and visualization of the structural change by atomic-force microscopy (AFM) provided information on the type and route of molecular interaction of drug construction with lipid layers. The possible role of electrostatic interactions between lipid layer and drug candidates was tested in Langmuir-balance experiments using negatively charged lipid mixture (DPPC+DPPG). Especially the peptide conjugates presented increased membrane affinity due to cationic character of the peptide sequence selected for the conjugate formation. That is supposed to be one reason for the enhanced cellular uptake observed in vitro for MonoMac6 cell line. The conjugation of antitubercular agents to a peptidic carrier is a promising approach to enhance membrane affinity, cellular uptake rate and in vitro selectivity.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
Q Science / természettudomány > QR Microbiology / mikrobiológia
Depositing User: Dr Katalin Uray
Date Deposited: 29 Sep 2016 12:16
Last Modified: 04 Apr 2023 11:44
URI: http://real.mtak.hu/id/eprint/40483

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