Oral Presentation 11th Australian Peptide Conference 2015

Intracellular targeting by oligo- or polypeptide conjugates (#50)

Ferenc Hudecz 1 , Rita Szabó 2 , Erika Orbán 2 , Kata Horváti 2 , Szilvia Bősze 2 , Gábor Mező 2
  1. Organic Chemistry, Eötvös L. University (ELTE), Budapest, Hungary
  2. Research Group of Peptide Chemistry, P.O.Box 32, Budapest 112, H-1518 , Eötvös L. University, Hungarian Academy of Sciences,, Budapest

Approaches based on “passive targeting” are to deliver bioactive entity directly to the cells involved by covalent peptide conjugate. We have developed two groups of conjugates in which drugs (e.g. daunomycin, methotrexate, vinblastin, isoniazid or enzyme inhibitor) are coupled either to branched chain polymeric polypeptides, (poly[Lys-(DL-Alam-Xi)] (X = Glu, Ser) with different charge characteristics or to cell penetrating oligopeptides. Polypeptide carriers with polylysine backbone has been shown to enhance the effect of anti-tumour and anti-parasitic drugs reducing non-specific toxicity, altering pharmacokinetics, immunogenicity. Charge, polarity and position in the branches of the amino-acid constituent X are also able to influence the membrane reactivity and in vivo biodistribution. Oligoarginines, as cell-penetrating peptides, can transport covalently attached compounds into different kinds of cells and enhance the efficiency. We observed that the fluorescent properties, cytostatic/cytotoxic effect on various cells (e.g. HL-60, HepG2, COS7) as well as the uptake properties, determined under different conditions (time, concentration) of Argn-conjugates could be different and dependent on the covalent linkage applied between the two entities. We found that attachment of oligopeptide/polypeptide to the bioactive agent could alter protein expression profile, significantly improve the anti-tumour, anti-parasitic or anti-tubercular activity of the drug. 

Acknowledgements: These studies were supported by grants from Hungarian Research Fund (K104385, PD-83923).

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