Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
National Centre for Innovative Technologies in Public Health, National Institute of Health, Viale Regina Elena, 299, 00161 Rome, Italy.
Int J Mol Sci. 2023 Sep 19;24(18):14268. doi: 10.3390/ijms241814268.
Effective therapy against the influenza virus is still an unmet goal. Drugs with antiviral effects exist, but the appearance of resistant viruses pushes towards the discovery of drugs with different mechanisms of action. New anti-influenza molecules should target a good candidate, as a new anti-influenza molecule could be an inhibitor of the influenza A virus hemagglutinin (HA), which plays a key role during the early phases of infection. In previous work, we identified two tetrapeptide sequences, SLDC () and SKHS (), derived from bovine lactoferrin (bLf) C-lobe fragment 418-429, which were able to bind HA and inhibit cell infection at picomolar concentration. Considering the above, the aim of this study was to synthesize a new library of peptidomimetics active against the influenza virus. In order to test their ability to bind HA, we carried out a preliminary screening using biophysical assays such as surface plasmon resonance (SPR) and orthogonal immobilization-free microscale thermophoresis (MST). Biological and computational studies on the most interesting compounds were carried out. The methods applied allowed for the identification of a N-methyl peptide, S(N-Me)LDC, which, through high affinity binding of influenza virus hemagglutinin, was able to inhibit virus-induced hemagglutination and cell infection at picomolar concentration. This small sequence, with high activity, represents a good starting point for the design of new peptidomimetics and small molecules.
有效对抗流感病毒的疗法仍是一个未满足的目标。具有抗病毒作用的药物确实存在，但耐药病毒的出现促使人们去发现具有不同作用机制的药物。新的抗流感分子应该针对一个良好的候选物，因为新的抗流感分子可能是流感 A 病毒血凝素 (HA) 的抑制剂，HA 在感染的早期阶段发挥着关键作用。在之前的工作中，我们从牛乳铁蛋白 (bLf) C 结构域 418-429 片段中鉴定出两个四肽序列 SLDC()和 SKHS()，它们能够结合 HA 并在皮摩尔浓度下抑制细胞感染。鉴于上述情况，本研究的目的是合成针对流感病毒的新型肽模拟物文库。为了测试它们结合 HA 的能力，我们使用表面等离子体共振 (SPR) 和正交非固定微尺度热泳 (MST) 等生物物理测定法进行了初步筛选。对最有趣的化合物进行了生物学和计算研究。应用的方法鉴定出一种 N-甲基肽 S(N-Me)LDC，它通过与流感病毒血凝素的高亲和力结合，能够在皮摩尔浓度下抑制病毒诱导的血凝和细胞感染。这种具有高活性的小序列代表了设计新肽模拟物和小分子的良好起点。
