TY - ABST

T1 - Studies towards improved cell-penetrating peptide-promoted macromolecular drug delivery

AU - Dahlqvist Clausen, Jacob Andreas

AU - Linderoth, L.

AU - Andersen, R. B.

AU - Franzyk, Henrik

AU - Nielsen, Hanne Mørck

PY - 2010

Y1 - 2010

N2 - The general concept of drug delivery facilitated by cell-penetrating peptides (CPPs) is well-known; however its practical utility for delivery of biopharmaceuticals necessitates further development concerning in vivo stability and efficiency of these peptidic carriers. In the present project, the aim is to increase the stability towards enzymatic degradation as well as to improve membrane translocation properties by incorporating novel unnatural amino acids into the naturally occurring CPP penetratin. The CPP efficiency of these penetratin analogues will be tested upon conjugation to a therapeutic biomacromolecule. Nine novel and unique amino acid building blocks have been synthesized from enantiopure aziridines to form amino acids with additional cationic charges as compared to natural amino acids. An increased number of cationic charges in CPPs have been shown to improve the interaction between CPPs and the cell membrane. The novel amino acids will be incorporated into penetratin to increase its cationic charge and to generate more efficient and stable CPPs. The enzymatic stability of penetratin is estimated by testing its resistance towards degradation by intestinal juice from rats. The metabolites are analyzed by an Orbitrap MS to identify the initial sites of cleavage and the largest non-degradable fragment as well. Thereby the optimal sites for incorporation of the novel amino acids may be revealed. The modified penetratin molecules will be tested for stability and CPP efficiency.

AB - The general concept of drug delivery facilitated by cell-penetrating peptides (CPPs) is well-known; however its practical utility for delivery of biopharmaceuticals necessitates further development concerning in vivo stability and efficiency of these peptidic carriers. In the present project, the aim is to increase the stability towards enzymatic degradation as well as to improve membrane translocation properties by incorporating novel unnatural amino acids into the naturally occurring CPP penetratin. The CPP efficiency of these penetratin analogues will be tested upon conjugation to a therapeutic biomacromolecule. Nine novel and unique amino acid building blocks have been synthesized from enantiopure aziridines to form amino acids with additional cationic charges as compared to natural amino acids. An increased number of cationic charges in CPPs have been shown to improve the interaction between CPPs and the cell membrane. The novel amino acids will be incorporated into penetratin to increase its cationic charge and to generate more efficient and stable CPPs. The enzymatic stability of penetratin is estimated by testing its resistance towards degradation by intestinal juice from rats. The metabolites are analyzed by an Orbitrap MS to identify the initial sites of cleavage and the largest non-degradable fragment as well. Thereby the optimal sites for incorporation of the novel amino acids may be revealed. The modified penetratin molecules will be tested for stability and CPP efficiency.

U2 - 10.1016/j.drudis.2010.09.427

DO - 10.1016/j.drudis.2010.09.427

M3 - Conference abstract in journal

VL - 15

SP - 1109

JO - Drug Discovery Today: BIOSILICO

JF - Drug Discovery Today: BIOSILICO

SN - 1359-6446

IS - 23-24

M1 - A81

ER -