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

Horváti, Kata and Bacsa, B. and Szabó, N. and Fodor, K. and Balka, Gy. and Rusvai, M. and Kiss, É. and Mező, Gábor and Grolmusz, V. and Vértessy G., Beáta and Hudecz, Ferenc and Bősze, Szilvia (2015) Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models. TUBERCULOSIS, 95 (1). pp. 207-211. ISSN 1472-9792

Preview

Text Antimycobacterial_cikk_Horvati_Kata_Vertessy_u_101339.423886.pdf Download (374kB) | Preview

Abstract

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 relevant 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 proved: 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.

Actions (login required)

Edit Item