Comparative analysis of new peptide conjugates of antitubercular drug candidates-Model membrane and in vitro studies

Á Ábrahám; Zs Baranyai; G Gyulai; E Pári; K Horváti; Sz Bősze; É Kiss

doi:10.1016/j.colsurfb.2016.07.054

Comparative analysis of new peptide conjugates of antitubercular drug candidates-Model membrane and in vitro studies

Colloids Surf B Biointerfaces. 2016 Nov 1:147:106-115. doi: 10.1016/j.colsurfb.2016.07.054. Epub 2016 Jul 28.

Authors

Á Ábrahám¹, Zs Baranyai², G Gyulai¹, E Pári¹, K Horváti², Sz Bősze², É Kiss³

Affiliations

¹ Laboratory of Interfaces and Nanostructures, Institute of Chemistry, Eötvös Loránd University, Budapest 112, PO Box 32, H-1518 Budapest, Hungary.
² MTA-ELTE Research Group of Peptide Chemistry, Budapest 112, P.O. Box 32, H-1518 Budapest, Hungary.
³ Laboratory of Interfaces and Nanostructures, Institute of Chemistry, Eötvös Loránd University, Budapest 112, PO Box 32, H-1518 Budapest, Hungary. Electronic address: kisseva@chem.elte.hu.

PMID: 27497074
DOI: 10.1016/j.colsurfb.2016.07.054

Abstract

Novel peptide conjugates of two antitubercular drug candidates were synthesised and characterised using new tuftsin peptide derivative (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 on 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.

Keywords: Antitubercular; Cellular uptake; Drug peptide conjugate; Lipid membrane models; Membrane affinity; Mycobacterium tuberculosis.

Publication types

Comparative Study

MeSH terms

Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Cell Survival / drug effects
Cells, Cultured
Drug Carriers / chemistry*
Drug Carriers / metabolism
Flow Cytometry
Humans
In Vitro Techniques
Lipid Bilayers / chemistry*
Lipid Bilayers / metabolism
Membranes, Artificial*
Microbial Sensitivity Tests
Microscopy, Atomic Force
Models, Molecular*
Monocytes / cytology*
Monocytes / drug effects
Mycobacterium tuberculosis / drug effects*
Peptide Fragments / chemistry
Peptide Fragments / pharmacology*

Substances

Antitubercular Agents
Drug Carriers
Lipid Bilayers
Membranes, Artificial
Peptide Fragments