In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S-enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) significantly more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. In addition, Mpro, as one of the critical enzymes for viral transcription and replication, also exhibited an enantioselective binding affinity toward the S-enantiomers. The most significant finding from this study is the pronounced difference of the two enantiomers of CQ and HCQ observed in hERG inhibition assay. The IC50 value of S-HCQ was higher than 20 μM against hERG channel, which was much less active over all tested CQ and HCQ compounds. Moreover, S-HCQ alone did not prolong QT interval in guinea pigs after 3 days and 6 days of administration, indicating a much lower cardiac toxicity potential. With these and previous findings on the enantio-differentiated metabolism, we recommend that future clinical studies should employ S-HCQ, substantially free of the R-enantiomer, to potentially improve the therapeutic index for the treatment of COVID-19 over the racemic CQ and HCQ.

中文翻译：

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氯喹和羟氯喹的对映体在体外表现出对SARS-CoV-2的不同活性，证明S-羟氯喹是COVID-19的潜在优势药物

迄今为止，在所有针对COVID-19的临床试验中，以及正在进行的涉及氯喹或羟氯喹的临床试验中，所使用的药物始终是二磷酸氯喹（CQ）或硫酸羟氯喹（HCQ），即氯喹的磷酸或硫酸盐。 R和S对映体的外消旋混合物（50/50）。结果，先前的CQ或HCQ试验的临床结果实际上是具有固有的不同药效学和药代动力学特性以及毒性作用的R和S对映异构体的集体表现。我们的数据首次证明，在生物安全3级实验室中，CQ和HCQ对活SARS-CoV-2病毒的立体选择性不同。S-氯喹（S-CQ）和S-羟基氯喹（S-HCQ）对SARS-CoV-2的活性明显更高，与R-CQ和R-HCQ分别相比。另外，Mpro，作为病毒转录和复制的关键酶之一，还表现出对S-对映体的对映选择性结合亲和力。这项研究最重要的发现是在hERG抑制分析中观察到的CQ和HCQ两种对映异构体的显着差异。针对hERG通道，S-HCQ的IC50值高于20μM，在所有测试的CQ和HCQ化合物中其活性均低得多。此外，单独使用S-HCQ并不能延长豚鼠给药3天和6天后的QT间隔，这表明其潜在的心脏毒性要低得多。鉴于这些和​​先前对映体分化代谢的发现，我们建议以后的临床研究应使用基本上不含R对映体的S-HCQ，