Gilead Sciences, Inc., Foster City, CA 94404, USA.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Molecules. 2022 Jun 30;27(13):4212. doi: 10.3390/molecules27134212.
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.
为应对 COVID-19 大流行，我们需要加速评估许多已批准的药物，以寻找针对致病病原体——严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的潜在抗病毒药物。我们采用基于细胞的生化和建模方法，研究了已批准的 HIV-1 核苷/核苷酸逆转录酶抑制剂（NRTIs）替诺福韦（TFV）和恩曲他滨（FTC），以及前药替诺福韦艾拉酚胺（TAF）和替诺福韦富马酸酯（TDF），以评估它们对 SARS-CoV-2 的抗病毒作用。一整套体外数据表明，TFV、TAF、TDF 和 FTC 对 SARS-CoV-2 均无活性。在高达 50 µM 的 TAF、TDF、FTC 或 500 µM 的 TFV 浓度下，NRTIs 均未显示在感染 SARS-CoV-2 的 A549-hACE2 细胞或原代正常人肺支气管上皮（NHBE）细胞中具有抗病毒活性。这些结果与 SARS-CoV-2 RNA 依赖性-RNA 聚合酶（RdRp）对相应 NTP 类似物的低掺入效率以及缺乏 RdRp 抑制作用相符。结构建模进一步表明，这些 NRTI 活性代谢物在 SARS-CoV-2 RdRp 活性部位的拟合情况较差。我们的数据表明，HIV-1 NRTIs 不太可能是 SARS-CoV-2 的直接抗病毒药物，临床医生和研究人员在探索使用这些和其他 NRTIs 治疗或预防 COVID-19 的想法时应谨慎行事。
