Synthetic saponins as inhibitors of virus:DC-SIGN interactions

艾滋病毒感染是世界范围内的一个重大健康问题。目前的抗逆转录病毒疗法在帮助艾滋病毒患者存活方面是有效的，但在完全清除体内病毒方面仍然无效，并可能导致不良副作用，如残留炎症。因此，针对艾滋病毒的新的抗病毒战略是可取的，这是该项目的主要重点。人类免疫缺陷病毒(HIV)可以通过DC-SIGN受体与人树突状细胞结合，该受体是某些碳水化合物(即Lewis-X抗原)的特异性受体。我们建议用化学方法制备含有Lewis-X抗原的天然化合物(即皂苷)，这些化合物是无毒的，很容易从桦树皮残渣中获得，并且能够自组装成胶束。我们将评估这些化合物在分子和超分子形式下与DC-SIGN受体结合的能力，并在细胞模型中抑制DC-SIGN介导的HIV感染。该项目将提供关于糖部分如何影响皂苷自组装能力的新的基础知识，以及如何利用这些合成结构来探测和抑制HIV与临床上至关重要的人类免疫受体的相互作用。最终，拟议的研究项目将使人们能够接触到一类新的试剂，帮助预防艾滋病毒感染。

HIV infections are a significant health issue worldwide. Current antiretroviral therapy is efficient in helping HIV patients to survive, however it remains ineffective in completely removing the virus from the body and can cause undesirable side effects such as residual inflammation. New antiviral strategies against HIV are thus desirable, which is the main focus of this project. Human immunodeficiency virus (HIV) can bind to human dendritic cells through the DC-SIGN receptor, which is specific to certain carbohydrates (i.e., Lewis-X antigens). We propose to chemically prepare natural compounds (i.e., saponins) bearing Lewis-X antigens, which are non-toxic, readily accessible from birch bark residues, and able to self-assemble into micelles. We will evaluate the capacity of these compounds, in both their molecular and supramolecular forms, to bind with the DC-SIGN receptor and to inhibit the DC-SIGN-mediated HIV infection in cellular models. The project will provide new fundamental knowledge on how sugar moieties affect the capacity of saponins to self-assemble and how these synthetic structures could be used to probe and inhibit the interaction of HIV with a human immune receptor of crucial clinical importance. Ultimately, the proposed research project will give access to a new class of agents to help protect against HIV infection.