Harfoot Rhodri, Lawley Blair, Hernández Leonor C, Kuang Joanna, Hills Francesca R, Sinha Shubhra, Allais Margot J M, Bird Tom W, Hird Cody P, Taylor John A, Bostina Mihnea, Comoletti Davide, Haney Evan F, Hancock Robert E W, Pletzer Daniel, Quiñones-Mateu Miguel E
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Pediatric Dentistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Antimicrob Agents Chemother. 2025 Jun 23:e0170024. doi: 10.1128/aac.01700-24.
Although myriads of potential antiviral agents have been tested against SARS-CoV-2, only a handful have proven to be effective in clinical trials. During the COVID-19 pandemic, many known or novel peptides were evaluated for their ability to inhibit SARS-CoV-2 replication; however, testing of D-enantiomers that resist body and viral proteases has been limited. Here, we characterized the ability of D-3006, a D-enantiomeric synthetic host defense peptide, to inhibit SARS-CoV-2 replication . A battery of authentic SARS-CoV-2 variants (ancestral, Mu, Delta, and Omicron BA.1) and a comprehensive panel of β-coronavirus spike pseudotyped lentiviruses were used to demonstrate that D-3006 safely (CCvalue = 430 µg/mL) blocked spike-mediated entry (EC values ranging from 1.57 to 5.37 µg/mL) and also had synergistic anti-SARS-CoV-2 activity when combined with the viral polymerase inhibitor remdesivir. We also showed that D-3006 inhibited influenza A virus (H1N1) replication , suggesting that this synthetic host defense peptide could have potential broad antiviral activity against multiple enveloped viruses. These data, together with negative-stain transmission electron microscopy analysis, suggest that the mechanism of action of D-3006 is associated with non-specific binding to the viral membrane, most likely causing virus aggregation and interfering with virus attachment and entry. The potential broad-spectrum antiviral activity of D-3006, its innate resistance to host proteases, as well as the possibility of being used in combination with other antiviral drugs suggest that this host synthetic peptide could be developed as a candidate for the treatment of SARS-CoV-2 and/or other respiratory viral infections.
尽管已经针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）测试了无数潜在的抗病毒药物，但只有少数几种在临床试验中被证明是有效的。在冠状病毒病（COVID-19）大流行期间，许多已知或新型肽被评估了抑制SARS-CoV-2复制的能力；然而，对抵抗人体和病毒蛋白酶的D-对映体的测试一直有限。在此，我们表征了一种D-对映体合成宿主防御肽D-3006抑制SARS-CoV-2复制的能力。使用一系列正宗的SARS-CoV-2变体（原始毒株、缪毒株、德尔塔毒株和奥密克戎BA.1毒株）以及一组全面的β冠状病毒刺突假型慢病毒，以证明D-3006安全地（半数细胞毒性浓度值=430微克/毫升）阻断刺突介导的进入（半数有效浓度值范围为1.57至5.37微克/毫升），并且在与病毒聚合酶抑制剂瑞德西韦联合使用时还具有协同抗SARS-CoV-2活性。我们还表明D-3006抑制甲型流感病毒（H1N1）复制，这表明这种合成宿主防御肽可能对多种包膜病毒具有潜在的广泛抗病毒活性。这些数据，连同负染透射电子显微镜分析，表明D-3006的作用机制与非特异性结合病毒膜有关，很可能导致病毒聚集并干扰病毒附着和进入。D-3006的潜在广谱抗病毒活性、其对宿主蛋白酶的固有抗性以及与其他抗病毒药物联合使用的可能性表明，这种宿主合成肽可被开发为治疗SARS-CoV-2和/或其他呼吸道病毒感染的候选药物。
