The COVID-19 pandemic threatens to overwhelm healthcare systems around the world. The only current FDA-approved treatment, which directly targets the virus, is the ProTide prodrug remdesivir. In its activated form, remdesivir prevents viral replication by inhibiting the essential RNA-dependent RNA polymerase. Like other ProTide prodrugs, remdesivir contains a chiral phosphorus center. The initial selection of the (S_P)-diastereomer for remdesivir was reportedly due to the difficulty in producing the pure (R_P)-diastereomer of the required precursor. However, the two currently known enzymes responsible for the initial activation step of remdesivir are each stereoselective and show differential tissue distribution. Given the ability of the COVID-19 virus to infect a wide array of tissue types, inclusion of the (R_P)-diastereomer may be of clinical significance. To help overcome the challenge of obtaining the pure (R_P)-diastereomer of remdesivir, we have developed a novel chemoenzymatic strategy that utilizes a stereoselective variant of the phosphotriesterase from Pseudomonas diminuta to enable the facile isolation of the pure (R_P)-diastereomer of the chiral precursor for the chemical synthesis of the (R_P)-diastereomer of remdesivir.

中文翻译：

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抗病毒前药瑞德西韦 (RP) 异构体的化学酶法合成。

COVID-19 大流行可能会压垮世界各地的医疗系统。目前 FDA 批准的唯一直接针对病毒的治疗方法是 ProTide 前药瑞德西韦。在其激活形式下，瑞德西韦通过抑制必需的 RNA 依赖性 RNA 聚合酶来防止病毒复制。与其他 ProTide 前药一样，瑞德西韦含有手性磷中心。据报道，最初选择瑞德西韦的 ( SP )-非对映体是因为难以生产所需前体的纯 ( RP )-_{非对映体。}然而，目前已知的负责瑞德西韦初始激活步骤的两种酶均具有立体选择性，并显示出不同的组织分布。鉴于 COVID-19 病毒能够感染多种组织类型，包含 ( RP ) _-非对映异构体可能具有临床意义。_{为了帮助克服}获得瑞德西韦纯 ( RP )-非对映异构体的挑战，我们开发了一种新型化学酶策略，利用来自假单胞菌的磷酸三酯酶的立体选择性变体，能够轻松分离纯 ( RP )-非对映异构体用于化学合成瑞德西韦 ( RP ₎ -非对映异构体的手性前体。