Triple helix-forming oligonucleotides conjugated to indolocarbazole poisons direct topoisomerase I-mediated DNA cleavage to a specific site

Citation
Pb. Arimondo et al., Triple helix-forming oligonucleotides conjugated to indolocarbazole poisons direct topoisomerase I-mediated DNA cleavage to a specific site, BIOCONJ CHE, 12(4), 2001, pp. 501-509
Citations number
32
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOCONJUGATE CHEMISTRY
ISSN journal
10431802 → ACNP
Volume
12
Issue
4
Year of publication
2001
Pages
501 - 509
Database
ISI
SICI code
1043-1802(200107/08)12:4<501:THOCTI>2.0.ZU;2-2
Abstract
Topoisomerase I is an ubiquitous DNA-cleaving enzyme and an important thera peutic target in cancer chemotherapy for camptothecins as well as for indol ocarbazole antibiotics such as rebeccamycin. To achieve a sequence-specific cleavage of DNA by topoisomerase I, a triple helix-forming oligonucleotide was covalently linked to indolocarbazole-type topoisomerase I poisons. The three indolocarbazole-oligonucleotide conjugates investigated were able to direct topoisomerase I cleavage at a specific site based upon sequence rec ognition by tripler formation. The efficacy of topoisomerase I-mediated DNA cleavage depends markedly on the intrinsic potency of the drug. We show th at DNA cleavage depends also upon the length of the linker arm between the tripler-forming oligonucleotide and the drug. Based on a known structure of the DNA-topoisomerase I complex, a molecular model of the oligonucleotide conjugates bound to the DNA-topoisomerase I complex was elaborated to facil itate the design of a potent topoisomerase I inhibitor-oligonucleotide conj ugate with an optimized linker between the two moieties. The resulting olig onucleotide-indolocarbazole conjugate at 10 nM induced cleavage at the trip le helix site a-fold more efficiently than 5 muM of free indolocarbazole, w hile the other drug-sensitive sites were not cleaved. The rational design o f drug-oligonucleotide conjugates carrying a DNA topoisomerase poison may b e exploited to improve the efficacy and selectivity of chemotherapeutic can cer treatments by targeting specific genes and reducing drug toxicity.