Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Institute of Physical Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, 321004, China.
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Institute of Physical Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, 321004, China.
Anal Chim Acta. 2022 Jan 15;1190:339265. doi: 10.1016/j.aca.2021.339265. Epub 2021 Nov 13.
Trinucleotide repeats (TRs) with abnormal lengths and atypical folding are implicated in various neurodegenerative diseases. The least stable cytosine-cytosine (C-C) mismatches in TRs when structuring into homoduplexes/hairpins have more chance in certain sequence contexts to preferentially adopt an extrahelical (E-motif) conformation with respect to those in polarity-inverted intrahelical counterparts. Herein, we designed a trihydroxyphenyl porphyrin ligand (POH3) to meet the challenge towards resolving the E-motif conformation. POH3 exhibited a specific 2:1 binding with DNAs adopting the E-motif cytosine conformation, independent of the TRs length. The trihydroxyl pattern was very crucial to gain the E-motif selectivity over the polarity-inverted counterparts via the complementary hydrogen bonding that occurred in the minor groove. Our work first elucidates the rationale in designing ligands to selectively resolve the E-motif nucleotides within TRs.
三核苷酸重复（TRs）的异常长度和非典型折叠与各种神经退行性疾病有关。在形成同源双链体/发夹时，TRs 中最不稳定的胞嘧啶-胞嘧啶（C-C）错配在某些序列环境中更有可能优先采用额外螺旋（E-构象）构象，而不是极性反转的内环对应物。在此，我们设计了一种三羟基苯基卟啉配体（POH3），以应对解决 E-构象的挑战。POH3 与采用 E-构象胞嘧啶构象的 DNA 以 2:1 的比例结合，与 TRs 的长度无关。三羟基模式对于通过在小沟中发生的互补氢键获得对极性反转对应物的 E-构象选择性非常重要。我们的工作首次阐明了设计配体以选择性地解析 TRs 内的 E-构象核苷酸的基本原理。
