Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models.
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.
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary.
Kata
K
Horváti
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary.
Bernadett
B
Bacsa
Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Budapest, Hungary.
Nóra
N
Szabó
Department of State Veterinary Medicine and Agricultural Economics, Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Kinga
K
Fodor
Department of Pathology and Forensic Veterinary Medicine, Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Gyula
G
Balka
Department of Pathology and Forensic Veterinary Medicine, Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Miklós
M
Rusvai
Laboratory of Interfaces and Nanostructures, Eötvös L. University, Budapest, Hungary.
Éva
É
Kiss
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary.
Gábor
G
Mező
Protein Information Technology Group, Eötvös L. University, Budapest, Hungary.
Vince
V
Grolmusz
Institute of Enzimology, Hungarian Academy of Science, Budapest, Hungary.
Beáta
B
Vértessy
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary; Department of Organic Chemistry, Eötvös L. University, Budapest, Hungary.
Ferenc
F
Hudecz
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary. Electronic address: szilvia.bosze@gmail.com.
Szilvia
S
Bősze
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D058726:Nanoconjugates; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000494:pharmacology; D011091:Polyesters / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy*
C000606083:4-oxo-2-(pyrrolidin-1-yl)-pyrido(1,2-a)pyrimidine-3-carbaldehyde; D000995:Antitubercular Agents; D003692:Delayed-Action Preparations; D058726:Nanoconjugates; D014677:Pharmaceutical Vehicles; D011091:Polyesters; D011725:Pyridines; D011743:Pyrimidines; D011744:Pyrimidinones; D011759:Pyrrolidines; C033616:poly(lactide)
Guinea pig infection model; In silico docking; PLGA encapsulation; Peptide conjugate; Pyridopyrimidines