Natural and synthetic derivatives characterized by the presence of an anthraquinone nucleus represent an important class of antineoplastic agents whose mechanism of action is related to recognition of DNA and inhibition/poisoning of nucleic acid tracking enzymes. We report here the biological evaluation of anthraquinone-peptide conjugates where simple peptide sequences represent the basic elements for specific recognition of DNA regions of relevant importance in antineoplastic or antiviral chemotherapy. A first physiological relevant example is the nucleic acid multistrand structure assumed by G-rich DNA and RNA sequences, represented by G-quadruplex. These can be found at the end of each chromosome as well as in the promoter regions of several oncogenes. The selective stabilization of these peculiar arrangements can stop replication of cancerous cells thus finding application in chemotherapy. Anthraquinones (AQ) with side chains at the 2,6 positions have been previously found to bind preferentially to G-quadruplex structures. Several nucleic acid sequences and structures play also fundamental roles in early steps of viral replication. In particular, HIV-1 reverse transcriptase (RT) uses double stranded RNA sequences as well as DNA/RNA hybrids to perform its catalytic activities. The “R” regions of HIV-genome contain also highly structured RNA and DNA sequences (TAR and cTAR), which are selectively recognized by peptidyl-anthraquinones. Increasing the nucleic acid stability would decrease the efficiency of strand transfer steps by RT and eventually the completion of reverse transcription: selective recognition of these sequences could lead to inhibition of HIV-1 replication. In this line of research we describe here the DNA binding of a series of 2,6 substituted anthraquinones toward G quadruplexes as well as toward HIV-1 relevant nucleic acids structures, by using the same technological platform, i.e. Fluorescence Quenching Assays (FRET probes coupled to thermal melting experiments). Our results demonstrate that anthraquinones exhibit different selectivity toward different targets, namely the human telomeric sequence formed by repeats of the hexanucleotide (TTAGGG), the Primer Binding Sequence (PBS) and the polypurine tract (PPT) of HIV-1, thus establishing the basis for the exploitation of these compounds as leads for different classes of chemotherapeutics.
Selective recognition of nucleic acids by peptidyl-anthraquinones
Alice Sosic;PALUMBO, MANLIO;SISSI, CLAUDIA;GATTO, BARBARA
2011
Abstract
Natural and synthetic derivatives characterized by the presence of an anthraquinone nucleus represent an important class of antineoplastic agents whose mechanism of action is related to recognition of DNA and inhibition/poisoning of nucleic acid tracking enzymes. We report here the biological evaluation of anthraquinone-peptide conjugates where simple peptide sequences represent the basic elements for specific recognition of DNA regions of relevant importance in antineoplastic or antiviral chemotherapy. A first physiological relevant example is the nucleic acid multistrand structure assumed by G-rich DNA and RNA sequences, represented by G-quadruplex. These can be found at the end of each chromosome as well as in the promoter regions of several oncogenes. The selective stabilization of these peculiar arrangements can stop replication of cancerous cells thus finding application in chemotherapy. Anthraquinones (AQ) with side chains at the 2,6 positions have been previously found to bind preferentially to G-quadruplex structures. Several nucleic acid sequences and structures play also fundamental roles in early steps of viral replication. In particular, HIV-1 reverse transcriptase (RT) uses double stranded RNA sequences as well as DNA/RNA hybrids to perform its catalytic activities. The “R” regions of HIV-genome contain also highly structured RNA and DNA sequences (TAR and cTAR), which are selectively recognized by peptidyl-anthraquinones. Increasing the nucleic acid stability would decrease the efficiency of strand transfer steps by RT and eventually the completion of reverse transcription: selective recognition of these sequences could lead to inhibition of HIV-1 replication. In this line of research we describe here the DNA binding of a series of 2,6 substituted anthraquinones toward G quadruplexes as well as toward HIV-1 relevant nucleic acids structures, by using the same technological platform, i.e. Fluorescence Quenching Assays (FRET probes coupled to thermal melting experiments). Our results demonstrate that anthraquinones exhibit different selectivity toward different targets, namely the human telomeric sequence formed by repeats of the hexanucleotide (TTAGGG), the Primer Binding Sequence (PBS) and the polypurine tract (PPT) of HIV-1, thus establishing the basis for the exploitation of these compounds as leads for different classes of chemotherapeutics.Pubblicazioni consigliate
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