Pharmacokinetics of Py-Im polyamides depend on architecture: cyclic versus linear.
نویسندگان
چکیده
The pharmacokinetic properties of three pyrrole-imidazole (Py-Im) polyamides of similar size and Py-Im content but different shape were studied in the mouse. Remarkably, hairpin and cyclic oligomers programmed for the same DNA sequence 5'-WGGWWW-3' displayed distinct pharmacokinetic properties. Furthermore, the hairpin 1 and cycle 2 exhibited vastly different animal toxicities. These data provide a foundation for design of DNA binding Py-Im polyamides to be tested in vivo.
منابع مشابه
Cyclic pyrrole-imidazole polyamides targeted to the androgen response element.
Hairpin pyrrole-imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor-DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an gamma-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cycl...
متن کاملSynthesis of Cyclic Py-Im Polyamide Libraries
Cyclic Py-Im polyamides containing two GABA turn units exhibit enhanced DNA binding affinity, but extensive studies of their biological properties have been hindered due to synthetic inaccessibility. A facile modular approach toward cyclic polyamides has been developed via microwave-assisted solid-phase synthesis of hairpin amino acid oligomer intermediates followed by macrocyclization. A focus...
متن کاملBinding of hairpin pyrrole and imidazole polyamides to DNA: relationship between torsion angle and association rate constants
N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides are small organic molecules that bind to DNA with sequence specificity and can be used as synthetic DNA-binding ligands. In this study, five hairpin eight-ring Py-Im polyamides 1-5 with different number of Im rings were synthesized, and their binding behaviour was investigated with surface plasmon resonance assay. It was found that associat...
متن کاملRational design of specific binding hairpin Py-Im polyamides targeting human telomere sequences.
N-Methylpyrrole (Py)-N-methylimidazole (Im) polyamides are organic molecules that can recognize predetermined DNA sequences in a sequence-specific manner. Human telomeres contain regions of (TTAGGG)n repetitive nucleotide sequences at each end of chromosomes, and these regions protect the chromosome from deterioration or from fusion with neighboring chromosomes. The telomeres are disposable buf...
متن کاملEfficient Synthesis of Peptide and Protein Functionalized Pyrrole-Imidazole Polyamides Using Native Chemical Ligation
The advancement of DNA-based bionanotechnology requires efficient strategies to functionalize DNA nanostructures in a specific manner with other biomolecules, most importantly peptides and proteins. Common DNA-functionalization methods rely on laborious and covalent conjugation between DNA and proteins or peptides. Pyrrole-imidazole (Py-Im) polyamides, based on natural minor groove DNA-binding ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of the American Chemical Society
دوره 134 18 شماره
صفحات -
تاریخ انتشار 2012