Ring-Fused Firefly Luciferins: Expanded Palette of Near-Infrared Emitting Bioluminescent Substrates
Ring-Fused Firefly Luciferins: Expanded Palette of Near-Infrared Emitting Bioluminescent Substrates
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DOI：
10.1021/acs.analchem.9b04562
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发表时间：
2020-03-17
影响因子：
7.4
通讯作者：
Citterio, Daniel
中科院分区：
文献类型：
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作者：
Ikeda, Yuma;Nomoto, Takahiro;Citterio, Daniel
萤火虫生物发光作为一种非侵入性成像方式广泛应用于生物医学研究领域。萤火虫生物发光成像的一个限制是在近红外 (NIR) 区域（650-900 nm）发射的荧光素种类有限，该区域的组织穿透性很高。在这里，我们描述了一系列结构固有的近红外发射萤火虫荧光素类似物，NIRLucs，通过环融合策略设计。这种策略导致天然萤火虫荧光素酶产生不依赖于 pH 值的结构固有的近红外发射，这在理论上得到了每种荧光素氧化形式的量子化学计算的支持。当应用于细胞时，即使在天然 n-荧光素底物不发射的低浓度下，NIRLuc 也表现出剂量依赖性的 NIR 发射改善。此外，在带有皮下肿瘤的小鼠中，使用一种 NIRLuc 观察到比 n-荧光素具有优异的血液保留和更亮的光子通量（总体为 7 倍，在 NIR 光谱范围内为 16 倍）。我们相信，这些合成荧光素为近红外发射荧光素品种的长期限制提供了解决方案，并为近红外生物发光成像平台的进一步发展铺平了道路。
Firefly bioluminescence is broadly applied as a noninvasive imaging modality in the biomedical research field. One limitation in firefly bioluminescence imaging is the limited variety of luciferins emitting in the near-infrared (NIR) region (650-900 nm), where tissue penetration is high. Herein, we describe a series of structure-inherent NIR emitting firefly luciferin analogues, NIRLucs, designed through a ring fusion strategy. This strategy resulted in pH-independent structure-inherent NIR emission with a native firefly luciferase, which was theoretically supported by quantum chemical calculations of the oxidized form of each luciferin. When applied to cells, NIRLucs displayed doseindependent improved NIR emission even at low concentrations where the native n-luciferin substrate does not emit. Additionally, excellent blood retention and brighter photon flux (7-fold overall, 16-fold in the NIR spectral range) than in the case of n-luciferin have been observed with one of the NIRLucs in mice bearing subcutaneous tumors. We believe that these synthetic luciferins provide a solution to the longstanding limitation in the variety of NIR emitting luciferins and pave the way to the further development of NIR bioluminescence imaging platforms.