禽流感是由A型流感病毒引起的一种对公共健康构成严重威胁的人畜共患传染病。目前使 用的药物只作用于M2离子通道和神经氨酸酶两个靶点，且面临日益严重的耐药性问题，因此迫切需要研制新的药物。我们前期的工作中发现多个肽类化合物（分子量<1000）具有较好的广谱抗流感病毒活性。这些化合物作用在血凝素酶HA2亚基的茎部，通过阻止HA2亚基在酸性条件下构象的变化进而阻止病毒进入宿主。此外，这些化合物还能降低宿主细胞NF-κB以及IL-1β, TNF-α等炎症因子的表达，因此具有免疫调节作用。以此为基础，本研究拟以流感病毒血凝素酶为靶点，对这些化合物进行深入的结构修饰和构效关系研究，以提高其抗病毒活性，尤其是通过构筑靶向复合肽的方法降低其毒性，提高其选择性，并深入探讨高活性化合物抗病毒及免疫调节作用的机制，为开发新型抗禽流感病毒药物打下基础。本研究的成功实施将对禽流感的治疗具有重要的意义。

Avian influenza is an infectious disease caused by influenza A viruses (IAV). It is a serious threat to public health. Thus far, there are only two types of drugs available in the clinics, which are M2 ion channel inhibitors and neuraminidase inhibitors. Nevertheless, the emergence of drug-resistant viral strains has been reported, thus it is imperative to develop new and effective anti-IAV drugs with different modes of action. In our previous work, we identified several short lipopeptides (MW<1000) possessing potent and broad anti-IAV activities. The mechanism study indicated that the binding site of these molecules is in the stem region of HA2 subunit of hemagglutinin (HA), by which to interrupt the conformational changes of HA2 and subsequently inhibit the fusion of virus-host cell membranes, thereby blocking the entry of virus. In addition, the study also showed that these peptides were able to reduce the level of NF-κB, as well as the expression of IL-1β and TNF-α, thus possessing the immunomodulatory ability towards host cells. On the basis of these works, this application will continue to investigate these lipopeptides by extensively modifying their structures and studying their structure-activity relationships, by which to obtain more potent candidates for the further investigation. The ongoing study will be carried out by targeting the influenza viral envelop protein of hemagglutinin (HA) and using H5N1 pseudo-typed virus as the screening model. To reduce the cellular toxicities and enhance the selectivity indices of these peptides, a strategy of “complex peptides” which we successfully developed recently will be employed. In addition, to make the candidates more valuable, the modes of action including anti-IAV and immunomodulatory activities will be extensively investigated, by which to establish a solid base for the development of new anti-IAV drugs. As a result, we believe that the successful implementation of this application will bring us one more choice for the treatment of avian influenza infection in the future.