Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation

Kata Horváti, Bernadett Bacsa, Nóra Szabó, Sándor Dávid, G. Mező, Vince Grolmusz, B. Vértessy, F. Hudecz, Sz. Bősze

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The therapy of tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M. tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5 antitubercular drug candidate to peptide carriers. As drug delivery components, (i) an antimicrobial granulysin peptide and (ii) a receptor specific tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5 coumarone derivative to the carrier peptides. The compounds were effective on M. tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20 tuftsin and GranF2 granulysin peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20 tuftsin conjugate exhibited significant antimycobacterial activity on M. tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria.

Original languageEnglish
Pages (from-to)900-907
Number of pages8
JournalBioconjugate Chemistry
Volume23
Issue number5
DOIs
Publication statusPublished - May 16 2012

Fingerprint

Computer Simulation
Tuftsin
Peptides
Mycobacterium tuberculosis
Antitubercular Agents
Bacteria
Macrophages
Drug Design
Pathogens
Antibiotics
Drug Delivery Systems
Bioinformatics
Computational Biology
Drug delivery
Metabolism
Pharmaceutical Preparations
Biological Availability
Tuberculosis
Therapeutics
Enzymes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Organic Chemistry
  • Pharmaceutical Science
  • Biomedical Engineering
  • Pharmacology

Cite this

Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation. / Horváti, Kata; Bacsa, Bernadett; Szabó, Nóra; Dávid, Sándor; Mező, G.; Grolmusz, Vince; Vértessy, B.; Hudecz, F.; Bősze, Sz.

In: Bioconjugate Chemistry, Vol. 23, No. 5, 16.05.2012, p. 900-907.

Research output: Contribution to journalArticle

Horváti, Kata ; Bacsa, Bernadett ; Szabó, Nóra ; Dávid, Sándor ; Mező, G. ; Grolmusz, Vince ; Vértessy, B. ; Hudecz, F. ; Bősze, Sz. / Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation. In: Bioconjugate Chemistry. 2012 ; Vol. 23, No. 5. pp. 900-907.
@article{8e795e4ae25f4f46a54e8f899d9d7fe5,
title = "Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation",
abstract = "Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The therapy of tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M. tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5 antitubercular drug candidate to peptide carriers. As drug delivery components, (i) an antimicrobial granulysin peptide and (ii) a receptor specific tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5 coumarone derivative to the carrier peptides. The compounds were effective on M. tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20 tuftsin and GranF2 granulysin peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20 tuftsin conjugate exhibited significant antimycobacterial activity on M. tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria.",
author = "Kata Horv{\'a}ti and Bernadett Bacsa and N{\'o}ra Szab{\'o} and S{\'a}ndor D{\'a}vid and G. Mező and Vince Grolmusz and B. V{\'e}rtessy and F. Hudecz and Sz. Bősze",
year = "2012",
month = "5",
day = "16",
doi = "10.1021/bc200221t",
language = "English",
volume = "23",
pages = "900--907",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation

AU - Horváti, Kata

AU - Bacsa, Bernadett

AU - Szabó, Nóra

AU - Dávid, Sándor

AU - Mező, G.

AU - Grolmusz, Vince

AU - Vértessy, B.

AU - Hudecz, F.

AU - Bősze, Sz.

PY - 2012/5/16

Y1 - 2012/5/16

N2 - Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The therapy of tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M. tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5 antitubercular drug candidate to peptide carriers. As drug delivery components, (i) an antimicrobial granulysin peptide and (ii) a receptor specific tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5 coumarone derivative to the carrier peptides. The compounds were effective on M. tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20 tuftsin and GranF2 granulysin peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20 tuftsin conjugate exhibited significant antimycobacterial activity on M. tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria.

AB - Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The therapy of tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M. tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5 antitubercular drug candidate to peptide carriers. As drug delivery components, (i) an antimicrobial granulysin peptide and (ii) a receptor specific tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5 coumarone derivative to the carrier peptides. The compounds were effective on M. tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20 tuftsin and GranF2 granulysin peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20 tuftsin conjugate exhibited significant antimycobacterial activity on M. tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria.

UR - http://www.scopus.com/inward/record.url?scp=84861109540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861109540&partnerID=8YFLogxK

U2 - 10.1021/bc200221t

DO - 10.1021/bc200221t

M3 - Article

VL - 23

SP - 900

EP - 907

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 5

ER -