Modulation of the pharmacokinetic properties of PNA:: Preparation of galactosyl, mannosyl, fucosyl, N-acetylgalactosaminyl, and N-acetylglucosaminyl derivatives of aminoethylglycine peptide nucleic acid monomers and their incorporation into PNA oligomers

被引:57
作者
Hamzavi, R
Dolle, F
Tavitian, B
Dahl, O
Nielsen, PE
机构
[1] Univ Copenhagen, Panum Inst, Dept Med Biochem & Genet, Ctr Biomol Recognit, DK-2200 Copenhagen N, Denmark
[2] Santaris Pharma AS, DK-2970 Horsholm, Denmark
[3] CEA, Serv Hosp Frederic Joliot, DSV, Dept Rech Med, F-91401 Orsay, France
[4] CEA, Serv Hosp Frederic Joliot, DSV, Dept Rech Med,INSERM,ERM 0103, F-91401 Orsay, France
[5] Univ Copenhagen, Dept Chem, DK-2100 Copenhagen 0, Denmark
关键词
D O I
10.1021/bc034022x
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
A series of N-(2-aminoethyl)-alpha-amino acid thymine peptide nucleic acid (PNA) monomers bearing glycosylated side chains in the a-amino acid position have been synthesized. These include PNA monomers where glycine has been replaced by serine and threonine (O-glycosylated), derivatives of lysine and nor-alanine (C-glycosylated), and amide derivatives of aspartic acid (N-glycosylated). The Boc and Fmoc derivatives of these monomers were used for incorporation in PNA oligomers. Twelve PNA decamers containing the glycosylated units in one, two, or three positions were prepared, and the thermal stability (T-m) of their complexes with a complementary RNA was determined. Incorporation of the glycosyl monomers reduced the duplex stability by 0-6 degreesC per substitution. A cysteine was attached to the amino terminus of eight of the PNA decamers (Cys-CTCATACTCT-NH2) for easy conjugation to a [F-18]radiolabeled N-(4-fluorobenzyl)-2-bromoacetamide. The in vivo biodistribution of these PNA oligomers was determined in rat 2 h after intravenous administration. Most of the radioactivity was recovered in the kidneys and in the urine. However, N-acetylgalactosamine (and to a lesser extent galactose and mannose)-modified PNAs were effectively targeting the liver (40-fold over unmodified PNA). Thus, the pharmacodistribution in rats of PNA oligomers can be profoundly changed by glycosylation. These results could be of great significance for PNA drug development, as they should allow modulation and fine-tuning of the pharmacokinetic profile of a drug lead.
引用
收藏
页码:941 / 954
页数:14
相关论文
共 42 条
[1]   Synthesis and activity of dipeptides, linked to targeting ligands, as specific NK cell enhancers [J].
Abbott, SD ;
Gagnon, L ;
Lagraoui, M ;
Kadhim, S ;
Attardo, G ;
Zacharie, B ;
Penney, CL .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (11) :1909-1926
[2]   Lectin-mediated drug targeting:: Selection of valency, sugar type (Gal/Lac), and spacer length for cluster glycosides as parameters to distinguish ligand binding to C-type asialoglycoprotein receptors and galectins [J].
André, S ;
Frisch, B ;
Kaltner, H ;
Desouza, DL ;
Schuber, F ;
Gabius, HJ .
PHARMACEUTICAL RESEARCH, 2000, 17 (08) :985-990
[3]  
Antopolsky M, 1999, HELV CHIM ACTA, V82, P2130, DOI 10.1002/(SICI)1522-2675(19991215)82:12<2130::AID-HLCA2130>3.0.CO
[4]  
2-A
[5]  
Augustyns K, 1998, J PEPT RES, V51, P127
[6]   Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes [J].
Biessen, EAL ;
Sliedregt-Bol, K ;
Hoen, PACT ;
Prince, P ;
Van der Bilt, E ;
Valentijn, ARPM ;
Meeuwenoord, NJ ;
Princen, H ;
Bijsterbosch, MK ;
Van der Marel, GA ;
Van Boom, JH ;
Van Berkel, TJC .
BIOCONJUGATE CHEMISTRY, 2002, 13 (02) :295-302
[7]   Novel antisense and peptide nucleic acid strategies for controlling gene expression [J].
Braasch, DA ;
Corey, DR .
BIOCHEMISTRY, 2002, 41 (14) :4503-4510
[8]   ANALOGS OF URIDINE 5'-DIPHOSPHATE GLUCOSE - INHIBITION OF GLYCOLIPID BIOSYNTHESIS [J].
BROXTERMAN, HJG ;
VANDERMAREL, GA ;
VANBOOM, JH .
TETRAHEDRON LETTERS, 1988, 29 (38) :4893-4896
[9]   Direct enantiomeric separation of N-aminoethylamino acids:: determination of the enantiomeric excess of chiral peptide nucleic acids (PNAs) by GC [J].
Corradini, R ;
Di Silvestro, G ;
Sforza, S ;
Palla, G ;
Dossena, A ;
Nielsen, PE ;
Marchelli, R .
TETRAHEDRON-ASYMMETRY, 1999, 10 (11) :2063-2066
[10]   AN EFFICIENT SYNTHESIS OF BOC-AMINOACETALDEHYDE AND ITS APPLICATION TO THE SYNTHESIS OF N-(2-BOC-AMINOETHYL)GLYCINE ESTERS [J].
DUEHOLM, KL ;
EGHOLM, M ;
BUCHARDT, O .
ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, 1993, 25 (04) :457-461