{"title":"MGB聚酰胺-寡核苷酸偶联物基因表达控制化合物的合成与评价。","authors":"Kazuo Kamaike, Mutsumi Sano, Daisuke Sakata, Yu Nishihara, Hiroaki Amino, Akihiro Ohtsuki, Yui Okada, Takafumi Miyakawa, Makoto Kogawara, Mai Tsutsumi, Misato Takahashi, Etsuko Kawashima, Koichiro Ota, Hiroaki Miyaoka","doi":"10.1155/2023/2447998","DOIUrl":null,"url":null,"abstract":"<p><p>MGB polyamide-oligonucleotide conjugates <b>ON 1</b>-<b>4</b> with linked MGB polyamides at the 2-exocyclic amino group of a guanine base using aminoalkyl linkers were synthesized and evaluated in terms of binding affinity for complementary DNA containing the MGB polyamide binding sequence using <i>T</i> <sub>m</sub> and CD analyses. The MGB polyamides comprised pyrrole polyamides (Py<sub>4</sub>- and Py<sub>3</sub>-), which possess binding affinity for A-T base pairs, and imidazole (Im<sub>3</sub>-) and pyrrole-<i>γ</i>-imidazole (Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-) polyamide hairpin motifs, which possess binding affinity for C-G base pairs. It was found that the stability of modified dsDNA was greatly influenced by the linker length. Py<sub>4</sub>- and Py<sub>3</sub>-oligonucleotide conjugates (<b>ON 1</b> (<i>n</i> = 4) and <b>ON 2</b> (<i>n</i> = 4)) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA. Although Im<sub>3</sub>-oligonucleotide conjugate <b>ON 3</b> (<i>n</i> = 4) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA, stabilization of dsDNA by the imidazole amide moiety of <b>ON 3</b> (<i>n</i> = 4) was lower compared with the pyrrole amide moiety of <b>ON 2</b> (<i>n</i> = 4). The Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-oligonucleotide conjugate <b>ON 4</b> (<i>n</i> = 2), which possesses binding affinity for C-G base pairs via a pyrrole/imidazole combination and contains a 2-aminoethyl linker, showed high binding ability for complementary DNA. Furthermore, the DNA sequence recognition of MGB polyamide-oligonucleotide conjugates was investigated using single-base mismatch DNAs, which possess a mismatch base in the MGB polyamide binding sequence. The Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-oligonucleotide conjugate <b>ON 4</b> (<i>n</i> = 2) showed high sequence recognition ability for complementary DNA.</p>","PeriodicalId":16575,"journal":{"name":"Journal of Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10030224/pdf/","citationCount":"1","resultStr":"{\"title\":\"Synthesis and Evaluation of MGB Polyamide-Oligonucleotide Conjugates as Gene Expression Control Compounds.\",\"authors\":\"Kazuo Kamaike, Mutsumi Sano, Daisuke Sakata, Yu Nishihara, Hiroaki Amino, Akihiro Ohtsuki, Yui Okada, Takafumi Miyakawa, Makoto Kogawara, Mai Tsutsumi, Misato Takahashi, Etsuko Kawashima, Koichiro Ota, Hiroaki Miyaoka\",\"doi\":\"10.1155/2023/2447998\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>MGB polyamide-oligonucleotide conjugates <b>ON 1</b>-<b>4</b> with linked MGB polyamides at the 2-exocyclic amino group of a guanine base using aminoalkyl linkers were synthesized and evaluated in terms of binding affinity for complementary DNA containing the MGB polyamide binding sequence using <i>T</i> <sub>m</sub> and CD analyses. The MGB polyamides comprised pyrrole polyamides (Py<sub>4</sub>- and Py<sub>3</sub>-), which possess binding affinity for A-T base pairs, and imidazole (Im<sub>3</sub>-) and pyrrole-<i>γ</i>-imidazole (Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-) polyamide hairpin motifs, which possess binding affinity for C-G base pairs. It was found that the stability of modified dsDNA was greatly influenced by the linker length. Py<sub>4</sub>- and Py<sub>3</sub>-oligonucleotide conjugates (<b>ON 1</b> (<i>n</i> = 4) and <b>ON 2</b> (<i>n</i> = 4)) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA. Although Im<sub>3</sub>-oligonucleotide conjugate <b>ON 3</b> (<i>n</i> = 4) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA, stabilization of dsDNA by the imidazole amide moiety of <b>ON 3</b> (<i>n</i> = 4) was lower compared with the pyrrole amide moiety of <b>ON 2</b> (<i>n</i> = 4). The Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-oligonucleotide conjugate <b>ON 4</b> (<i>n</i> = 2), which possesses binding affinity for C-G base pairs via a pyrrole/imidazole combination and contains a 2-aminoethyl linker, showed high binding ability for complementary DNA. Furthermore, the DNA sequence recognition of MGB polyamide-oligonucleotide conjugates was investigated using single-base mismatch DNAs, which possess a mismatch base in the MGB polyamide binding sequence. The Py<sub>3</sub>-<i>γ</i>-Im<sub>3</sub>-oligonucleotide conjugate <b>ON 4</b> (<i>n</i> = 2) showed high sequence recognition ability for complementary DNA.</p>\",\"PeriodicalId\":16575,\"journal\":{\"name\":\"Journal of Nucleic Acids\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10030224/pdf/\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Nucleic Acids\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1155/2023/2447998\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nucleic Acids","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1155/2023/2447998","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Synthesis and Evaluation of MGB Polyamide-Oligonucleotide Conjugates as Gene Expression Control Compounds.
MGB polyamide-oligonucleotide conjugates ON 1-4 with linked MGB polyamides at the 2-exocyclic amino group of a guanine base using aminoalkyl linkers were synthesized and evaluated in terms of binding affinity for complementary DNA containing the MGB polyamide binding sequence using Tm and CD analyses. The MGB polyamides comprised pyrrole polyamides (Py4- and Py3-), which possess binding affinity for A-T base pairs, and imidazole (Im3-) and pyrrole-γ-imidazole (Py3-γ-Im3-) polyamide hairpin motifs, which possess binding affinity for C-G base pairs. It was found that the stability of modified dsDNA was greatly influenced by the linker length. Py4- and Py3-oligonucleotide conjugates (ON 1 (n = 4) and ON 2 (n = 4)) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA. Although Im3-oligonucleotide conjugate ON 3 (n = 4) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA, stabilization of dsDNA by the imidazole amide moiety of ON 3 (n = 4) was lower compared with the pyrrole amide moiety of ON 2 (n = 4). The Py3-γ-Im3-oligonucleotide conjugate ON 4 (n = 2), which possesses binding affinity for C-G base pairs via a pyrrole/imidazole combination and contains a 2-aminoethyl linker, showed high binding ability for complementary DNA. Furthermore, the DNA sequence recognition of MGB polyamide-oligonucleotide conjugates was investigated using single-base mismatch DNAs, which possess a mismatch base in the MGB polyamide binding sequence. The Py3-γ-Im3-oligonucleotide conjugate ON 4 (n = 2) showed high sequence recognition ability for complementary DNA.