Wyniki wyszukiwania - Biblioteka Nauki

Nowa wersja platformy, zawierająca wyłącznie zasoby pełnotekstowe, jest już dostępna.
Przejdź na https://bibliotekanauki.pl

Ograniczanie wyników

2 Wiadomości Chemiczne

Znaleziono wyników: 2

Liczba wyników na stronie

Wyniki wyszukiwania

Wyszukiwano:
w słowach kluczowych: strategia antysensowa

Sortuj według:

Ogranicz wyniki do:

Koniugaty peptyd-oligonukleotyd : synteza i zastosowanie

100%

Kaczmarek R. , Radzikowska E. , Baraniak J.

tom [Z] 62, 11-12

1091-1113

Recently major advances have been made in the development of oligonucleotides as potential therapeutic agents [1-3]. However, a frequent limitation of their use is poor cellular uptake [5]. Among the many molecules that have been reported to enhance cell delivery of oligonucleotides there is a number of peptide carriers. They are preferably linked by covalent bond in many possible ways, resulting in a new class of compounds known as peptide-oligonucleotide conjugates (POCs) [6a, 9]. A variety of chemical linkages have been used to link the peptide and oligonucleotide fragments. A peptide can be conjugated either at the base-, 3'-, or 5'-position of the sugar unit or at the backbone of the oligonucleotide [10]. Similarly, the point of conjugation in a peptide can be either the C- or N-terminus or the side chain. Two different strategies have been adopted for the synthesis of POCs: in-line solid-phase synthesis (divergent method) and fragment conjugation (convergent method) [11]. In divergent method, the peptide and oligonucleotide fragments are assembled on automatic synthesizers, sequentially on the same solid support, until the final step. In predominant cases, the peptides are assembled first by the Fmoc method, while the oligonucleotides are assembled next using the phosphoramidite method [12]. In-line synthesis could be most direct for preparing POCs, but finding the right combination of protecting groups is the key problem. The first step in preparation of POCs involves modification of solid supports with suitable linkers [10]. A number of monofunctionalized as well as bifunctionalized linkers were immobilized over solid supports through suitable spacers (Figure 1). In the fragment conjugation, the peptide and oligonucleotide fragments are synthesized individually, cleaved from their solid supports, deprotected and purified, separately. Therefore, the most appropriate synthetic chemistry can be used for each component without concern for incompatibility. Both biopolimers are finally linked postsynthetically utilizing the reactive functional groups which are attached at the desired site of conjugation (Figure 4) [5]. If the postsynthetic conjugation is performed with one of the oligomers still joined to the solid phase, it is called the solid-phase fragment conjugation method. Alternatively, if the conjugation is effected after complete isolation and purification of the peptides and oligonucleotides, it is called fragment conjugation in the liquid phase [10]. Besides their potential use for therapeutic applications, POCs can serve as research tools, for example, as fluorescent probes [44] or PCR primers [25, 45]. With increased specificity and strength of target binding, POCs may be useful in diagnostic applications or as affinity purification reagents.

Modyfikowane oligodeoksyrybonukleotydy zawierające w wiązaniu internukleotydowym w pozycji mostkowej atom azotu

100%

Radzikowska E.

tom [Z] 67, 11-12

1003--1025

Synthetic oligonucleotides (ONs) constitute an important class of compounds which exhibit biological activity. As potential drugs ONs are employed in the antisense strategy [1]. The antisense therapeutic agent acts on the pathogenic mRNA causing inactivation of the target. Ideal antisense agent should be resistant to exo and/or endonucleases, have a suitable pharmacological and pharmacokinetic profile and high affinity for the target. To improve some properties of antisense oligonucleotides plethora of chemical modifications introduced within both sugar unit and internucleotides linkage were investigated. Among numerous ONs modified in internucleotide phosphodiester bond, one of the most interesting are oligonucleotide phosphoramidates (NP-oligos) in which one of the bridging oxygens is replaced by nitrogen atom (at 3’ or 5’ position). Hence, two classes of compounds are formed: oligonucleotide-(N5’→P3’)phosphoramidates and oligonucleotide(N3’→P5’)-phosphoramidates. These compounds, similar to native DNA and RNA, possess an achiral phosphorous atom and all internucleotides bonds are negatively charged. Additionally, NP-oligo shows good resistance to nucleolytic degradation and can bind to the target DNA or RNA with high affinity [12]. In literature several synthetic strategies concerning both (N5’→P3’) and (N3’→P5’) NP-oligos have been described. Some of them allowed to obtain only corresponding dimers. In the light of recent discoveries the most promising candidates for therapeutic and diagnostic applications are oligonucleotide-(N3’→P5’)thiophosphoramidates. Gryaznov et al. have found that such compounds can act as potent and selective telomerase inhibitors [29]. Human telomerase (TA) is a reverse transcriptase ribonucleoprotein that synthesizes de novo d-(TTAGGG)n repeats at chromosomal DNA ends. Whereas activity of this enzyme is observed in ~85% of all human tumors, most of normal somatic cells either lack TA activity or express it only at low levels. For these reasons TA constitute an attractive and nearly universal anticancer target for rational drug development.