Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 95; pp. S207 - S211
• Main Authors: Horváti, Kata, Bacsa, Bernadett, Szabó, Nóra, Fodor, Kinga, Balka, Gyula, Rusvai, Miklós, Kiss, Éva, Mező, Gábor, Grolmusz, Vince, Vértessy, Beáta, Hudecz, Ferenc, Bősze, Szilvia
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.06.2015
• Subjects: Animals; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacology; Delayed-Action Preparations; Disease Models, Animal; Female; Guinea pig infection model; Guinea Pigs; In silico docking; Infectious Disease; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Nanoconjugates; Peptide conjugate; Pharmaceutical Vehicles - administration & dosage; Pharmaceutical Vehicles - pharmacology; PLGA encapsulation; Polyesters - administration & dosage; Polyesters - pharmacology; Pulmonary/Respiratory; Pyridines - administration & dosage; Pyridines - pharmacology; Pyridopyrimidines; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Pyrimidinones - administration & dosage; Pyrimidinones - pharmacology; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacology; Tuberculosis - drug therapy; In silico docking; Pyridopyrimidines; Guinea pig infection model; Peptide conjugate; PLGA encapsulation
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2015.02.026

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 H37 Rv 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 H37 Rv 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.