Koniugaty peptyd-oligonukleotyd : synteza i zastosowanie

• Autorzy: Kaczmarek, R. , Radzikowska, E. , Baraniak, J.

Warianty tytułu

EN

Peptide-oligonucleotide conjugates: synthesis and applications

• Języki publikacji: PL

Abstrakty

EN

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.

Słowa kluczowe

PL

koniugaty peptyd-oligonukleotyd; synteza "ciągła" na fazie stałej; sprzęganie blokowe; łączniki; grupy ochronne; strategia antysensowa; zastosowania terapeutyczne

EN

peptide-oligonucleotide conjugates (POCs); in-line solid-phase synthesis; fragment conjugation; linker; protecting groups; antisense strategy; therapeutic applications

• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2008
• Tom: [Z] 62, 11-12
• Strony: 1091-1113
• Opis fizyczny: bibliogr. 47 poz., wykr.

Twórcy

autor

Kaczmarek, R.

autor

Radzikowska, E.

autor

Baraniak, J.

• Centrum Badań Molekularnych i Makromolekularnych Polskiej Akademii Nauk, Zakład Chemii Bioorganicznej, ul. Sienkiewicza 112, 90-362 Łódź,

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