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

被引：24

作者：

Horvati, Kata ^{[1
]}

Bacsa, Bernadett ^{[1
]}

Szabo, Nora ^{[2
]}

Fodor, Kinga ^{[3
]}

Balka, Gyula ^{[4
]}

Rusvai, Miklos ^{[4
]}

Kiss, Eva ^{[5
]}

Mezo, Gabor ^{[1
]}

Grolmusz, Vince ^{[6
]}

Vertessy, Beata ^{[7
]}

Hudecz, Ferenc ^{[1
,8
]}

Bosze, Szilvia ^{[1
]}

机构：

[1] Eotvos L Univ, Hungarian Acad Sci, MTA ELTE Res Grp Peptide Chem, H-1117 Budapest, Hungary

[2] Koranyi Natl Inst TB & Resp Med, Bacteriol Lab, Budapest, Hungary

[3] Szent Istvan Univ, Fac Vet Sci, Dept State Vet Med & Agr Econ, Budapest, Hungary

[4] Szent Istvan Univ, Fac Vet Sci, Dept Pathol & Forens Vet Med, Budapest, Hungary

[5] Eotvos L Univ, Lab Interfaces & Nanostruct, Budapest, Hungary

[6] Eotvos L Univ, Prot Informat Technol Grp, Budapest, Hungary

[7] Hungarian Acad Sci, Inst Enzimol, Budapest, Hungary

[8] Eotvos L Univ, Dept Organ Chem, Budapest, Hungary

来源：

TUBERCULOSIS | 2015年 / 95卷

关键词：

In silico docking; Pyridopyrimidines; Peptide conjugate; PLGA encapsulation; Guinea pig infection model; LIPOPEPTIDE CONJUGATE; PLGA MICROSPHERES; RIFAMPICIN; DELIVERY; SITE;

D O I：

10.1016/j.tube.2015.02.026

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 H(37)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 H(37)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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：S207 / S211

页数：5

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