Departamento de Física, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil.
Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil.
J Phys Chem B. 2022 May 19;126(19):3512-3521. doi: 10.1021/acs.jpcb.2c01119. Epub 2022 May 9.
Chloroquine (CLQ) and hydroxychloroquine (HCLQ) are compounds largely employed in the treatment of various human diseases for decades. Nevertheless, a number of intrinsic details concerning their mechanisms of action, especially at the molecular level, are still unknown or have presented controversial results in the literature. Using optical tweezers, here, we investigate at the single-molecule level the molecular mechanism of action of the drug CLQ in its intrinsic interaction with the double-stranded (ds)DNA molecule, one of its targets inside cells, determining the binding modes and the physicochemical (binding) parameters of the interaction. In particular, we show that the ionic strength of the surrounding medium strongly influences such interaction, changing even the main binding mode. In addition, the cytotoxicity of CLQ against three different cell lines was also investigated here, allowing one to evaluate and compare the effect of the drug on the cell viability. In particular, we show that CLQ is highly cytotoxic at a very low (a few micromolar) concentration range for all cell lines tested. These results were rigorously compared to the equivalent ones obtained for the closely related compound hydroxychloroquine (HCLQ), allowing a critical comparison between the action of these drugs at the molecular and cellular levels.
氯喹（CLQ）和羟氯喹（HCLQ）是几十年来广泛用于治疗各种人类疾病的化合物。然而，关于它们的作用机制，尤其是在分子水平上的许多内在细节，在文献中仍然未知或存在争议的结果。在这里，我们使用光学镊子在单分子水平上研究了药物 CLQ 与其内在的与双链（ds）DNA 分子相互作用的分子作用机制，这是其在细胞内的靶标之一，确定了相互作用的结合模式和物理化学（结合）参数。特别是，我们表明周围介质的离子强度强烈影响这种相互作用，甚至改变主要的结合模式。此外，还研究了 CLQ 对三种不同细胞系的细胞毒性，从而可以评估和比较药物对细胞活力的影响。特别是，我们表明 CLQ 在所有测试的细胞系中都具有非常高的细胞毒性，浓度非常低（几个微摩尔）。这些结果与密切相关的化合物羟氯喹（HCLQ）的等效结果进行了严格比较，允许在分子和细胞水平上对这些药物的作用进行批判性比较。
