Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models - 20/06/15

Doi : 10.1016/j.tube.2015.02.026

Kata Horváti ^a, Bernadett Bacsa ^a, Nóra Szabó ^b, Kinga Fodor ^c, Gyula Balka ^d, Miklós Rusvai ^d, Éva Kiss ^e, Gábor Mező ^a, Vince Grolmusz ^f, Beáta Vértessy ^g, Ferenc Hudecz ^a,^h, Szilvia Bősze ^a,^⁎
^a MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary
^b Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Budapest, Hungary
^c Department of State Veterinary Medicine and Agricultural Economics, Faculty of Veterinary Science, Szent István University, Budapest, Hungary
^d Department of Pathology and Forensic Veterinary Medicine, Faculty of Veterinary Science, Szent István University, Budapest, Hungary
^e Laboratory of Interfaces and Nanostructures, Eötvös L. University, Budapest, Hungary
^f Protein Information Technology Group, Eötvös L. University, Budapest, Hungary
^g Institute of Enzimology, Hungarian Academy of Science, Budapest, Hungary
^h Department of Organic Chemistry, Eötvös L. University, Budapest, Hungary

^∗Corresponding author. MTA-ELTE Research Group of Peptide Chemistry, Pázmány P. stny. 1/A, Budapest, 1117, Hungary. Tel.: +36 1 372 2500x1736; fax: +36 1 372 2620.

Summary

New pyridopyrimidine derivatives were defined using a novel HTS in silico docking method (FRIGATE). The target protein was a dUTPase enzyme (EC 3.6.1.23; Rv2697) which plays a key role in nucleotide biosynthesis of Mycobacterium tuberculosis (Mtb). Top hit molecules were assayed in vitro for their antimycobacterial effect on Mtb H₃₇Rv culture. In order to enhance the cellular uptake rate, the TB820 compound was conjugated to a peptid-based carrier and a nanoparticle type delivery system (polylactide-co-glycolide, PLGA) was applied. The conjugate had relevance to in vitro antitubercular activity with low in vitro and in vivo toxicity. In a Mtb H₃₇Rv infected guinea pig model the in vivo efficacy of orally administrated PLGA encapsulated compound was proven: animals maintained a constant weight gain and no external clinical signs of tuberculosis were observed. All tissue homogenates from lung, liver and kidney were found negative for Mtb, and diagnostic autopsy showed that no significant malformations on the tissues occurred.

Le texte complet de cet article est disponible en PDF.

Keywords : In silico docking, Pyridopyrimidines, Peptide conjugate, PLGA encapsulation, Guinea pig infection model

Plan

Introduction

Materials and methods

Synthesis and characterization of PLGA encapsulated pal-T5(TB820)₂

In vitro tests

In vivo evaluation

Results and discussion

In vitro antitubercular effect, cytotoxicity and hemolytic activity

In vivo toxicology and chemotherapeutic effect of PLGA-pT820

Export

Vol 95 - N° S1

P. S207-S211 - juin 2015 Retour au numéro

Article précédent

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library
Anna Sipos, János Pató, Rita Székely, Ruben C. Hartkoorn, László Kékesi, László ?rfi, Csaba Szántai-Kis, Katarína Mikušová, Zuzana Svetlíková, Jana Korduláková, Valakunja Nagaraja, Adwait Anand Godbole, Natassja Bush, Frédéric Collin, Anthony Maxwell, Stewart T. Cole, György Kéri

| Article suivant

Consolidated Action Plan to Prevent and Combat Multidrug- and Extensively Drug-resistant Tuberculosis in the WHO European Region 2011–2015: Cost-effectiveness analysis
Zsuzsanna Jakab, Colleen D. Acosta, Hans H. Kluge, Masoud Dara

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models - 20/06/15

Summary

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL