Tietjen Ian, Kwan Daniel C, Petrich Annett, Zell Roland, Antoniadou Ivi Theodosia, Gavriilidou Agni, Tzitzoglaki Christina, Rallis Michail, Fedida David, Sureda Francesc X, Mestdagh Cato, Naesens Lieve, Chiantia Salvatore, Johnson F Brent, Kolocouris Antonios
The Wistar Institute, Philadelphia, PA, 19104, USA; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Antiviral Res. 2025 Apr;236:106104. doi: 10.1016/j.antiviral.2025.106104. Epub 2025 Feb 11.
To better manage seasonal and pandemic influenza infections, new drugs are needed with enhanced activity against amantadine- and rimantadine-resistant influenza A virus (IAV) strains containing the S31N variant of the viral M2 ion channel (M2). Here we tested 36 amantadine analogs against a panel of viruses containing either M2 or the parental, M2 S31 wild-type variant (M2). We found that several analogs, primarily those with sizeable lipophilic adducts, inhibited up to three M2-containing viruses with activities at least 5-fold lower than rimantadine, without inhibiting M2 proton currents or modulating endosomal pH. While M2 viruses in passaging studies rapidly gained resistance to these analogs through the established M2 mutations V27A and/or A30T, resistance development was markedly slower for M2 viruses and did not associate with additional M2 mutations. Instead, a subset of analogs, exemplified by 2-propyl-2-adamantanamine (38), but not 2-(1-adamantyl)piperidine (26), spiro[adamantane-2,2'-pyrrolidine] (49), or spiro[adamantane-2,2'-piperidine] (60), inhibited cellular entry of infectious IAV following pre-treatment and/or H1N1 pseudovirus entry. Conversely, an overlapping subset of the most lipophilic analogs including compounds 26, 49, 60, and others, disrupted viral M2-M1 protein colocalization required for intracellular viral assembly and budding. Finally, a pilot toxicity study in mice demonstrated that 38 and 49 were tolerated at 30 mg/kg. Together, these results indicate that amantadine analogs act on multiple, complementary mechanisms to inhibit replication of M2 viruses.
为了更好地管理季节性流感和大流行性流感感染，需要研发新型药物，以增强对含病毒M2离子通道（M2）S31N变体的金刚烷胺和金刚乙胺耐药甲型流感病毒（IAV）毒株的活性。在此，我们针对一组含有M2或亲本M2 S31野生型变体（M2）的病毒，测试了36种金刚烷胺类似物。我们发现，几种类似物，主要是那些带有相当大的亲脂性加合物的类似物，可抑制多达三种含M2的病毒，其活性比金刚乙胺低至少5倍，且不抑制M2质子电流或调节内体pH值。虽然在传代研究中，M2病毒通过已确定的M2突变V27A和/或A30T迅速对这些类似物产生耐药性，但M2病毒的耐药性发展明显较慢，且与其他M2突变无关。相反，以2-丙基-2-金刚烷胺（38）为例的一部分类似物，但不是2-（1-金刚烷基）哌啶（26）、螺[金刚烷-2,2'-吡咯烷]（49）或螺[金刚烷-2,2'-哌啶]（60），在预处理后可抑制感染性IAV的细胞内进入和/或H1N1假病毒进入。相反，包括化合物26、49、60等在内的亲脂性最强的类似物的一个重叠子集，破坏了细胞内病毒组装和出芽所需的病毒M2-M1蛋白共定位。最后，在小鼠中进行的初步毒性研究表明，38和49在30mg/kg的剂量下是可耐受的。总之，这些结果表明金刚烷胺类似物通过多种互补机制抑制M2病毒的复制。
