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

Tuberculosis
Kata HorvátiSzilvia Bősze

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 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.

References

Jun 4, 2008·Biochemical and Biophysical Research Communications·Balázs VargaBeáta G Vértessy

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Citations

May 25, 2016·Biochimica Et Biophysica Acta. General Subjects·Kinga Nyíri, Beáta G Vértessy
Jan 30, 2018·Current Medicinal Chemistry·Alina MiniasJarosław Dziadek
Feb 8, 2020·Future Medicinal Chemistry·Krishna KurthkotiUmesh Varshney
Oct 31, 2020·Nucleic Acids Research·Balázs BaloghIstván M Mándity
Mar 7, 2021·International Journal of Molecular Sciences·Nikoletta KósaLevente Herenyi
Apr 7, 2017·European Journal of Medicinal Chemistry·Zsuzsa BaranyaiSzilvia Bősze

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