Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Dalton Trans. 2021 Mar 2;50(8):2757-2765. doi: 10.1039/d0dt04290k.
The adoption of compounds that target metalloenzymes comprises a relatively low (<5%) percentage of all FDA approved therapeutics. Metalloenzyme inhibitors typically coordinate to the active site metal ions and therefore contain ligands with charged or highly polar functional groups. While these groups may generate highly water-soluble compounds, this functionalization can also limit their pharmacological properties. To overcome this drawback, drug candidates can be formulated as prodrugs. While a variety of protecting groups have been developed, increasing efforts have been devoted towards the use of caging groups that can be removed upon exposure to light to provide spatial and temporal control over the treatment. Among these, the application of Ru(ii) polypyridine complexes is receiving increased attention based on their attractive biological and photophysical properties. Herein, a conjugate consisting of a metalloenzyme inhibitor and a Ru(ii) polypyridine complex as a photo-cage is presented. The conjugate was designed using density functional theory calculations and docking studies. The conjugate is stable in an aqueous solution, but irradiation of the complex with 450 nm light releases the inhibitor within several minutes. As a model system, the biochemical properties were investigated against the endonucleolytic active site of the influenza virus. While showing no inhibition in the dark in an in vitro assay, the conjugate generated inhibition upon light exposure at 450 nm, demonstrating the ability to liberate the metalloenzyme inhibitor. The presented inhibitor-Ru(ii) polypyridine conjugate is an example of computationally-guided drug design for light-activated drug release and may help reveal new avenues for the prodrugging of metalloenzyme inhibitors.
金属酶靶标的化合物的应用在所有获得美国食品和药物管理局（FDA）批准的治疗药物中仅占相对较低的（<5%）比例。金属酶抑制剂通常与活性位点金属离子配位，因此含有带有电荷或高极性官能团的配体。虽然这些基团可以生成高度水溶性的化合物，但这种功能化也可以限制它们的药理性质。为了克服这一缺点，可以将候选药物制成前药。虽然已经开发出了各种保护基团，但越来越多的努力致力于使用笼蔽基团，这些基团在暴露于光下时可以被去除，从而提供对治疗的空间和时间控制。在这些方法中，基于其吸引人的生物学和光物理性质，Ru(ii)多吡啶配合物的应用受到了越来越多的关注。本文提出了一种由金属酶抑制剂和 Ru(ii)多吡啶配合物作为光笼的轭合物。该轭合物是使用密度泛函理论计算和对接研究设计的。在水溶液中，轭合物是稳定的，但用 450nm 光照射复合物可在几分钟内释放出抑制剂。作为模型系统，研究了其在针对流感病毒内切核酸酶活性部位的生化性质。在体外测定中，黑暗条件下没有抑制作用，但在 450nm 光照射下，轭合物产生了抑制作用，证明了释放金属酶抑制剂的能力。所提出的抑制剂-Ru(ii)多吡啶轭合物是用于光激活药物释放的计算指导药物设计的一个例子，可能有助于为金属酶抑制剂的前药化揭示新的途径。
