Antiviral Synergism of Inhibitors Targeting HIV-1 Env and Host Cell Co-Receptors

描述(申请人提供)：本研究项目是中国科学院上海分院和费城德雷克塞尔大学的实验室联合开展的，旨在开发针对细胞进入的新型HIV-1抑制剂，并调查HIV-1 Env拮抗剂和宿主细胞共受体拮抗剂可以协同组合的潜在假设，以提高抗病毒活性和降低对功能受损病毒耐药性的易感性。仍然迫切需要艾滋病毒-1干预的新制剂，以减少艾滋病在全球发生和传播的影响。HIV-1对宿主细胞的感染是由暴露在宿主细胞表面的包膜蛋白复合体相互作用而启动的 病毒有两个细胞受体，即CD4和一个共同受体，最常见的是CCR5和CXCR4。在我们合作的实验室中，我们一直在研究能够灭活病毒以及CCR5和CXCR4共同受体拮抗剂的新型三氮唑gp120拮抗剂。先前的研究和我们自己的初步结果表明，协同作用的抑制剂靶向 Env和辅受体可以改善这些类型的抑制剂在预防和治疗干预中的潜在用途。这些进入抑制剂的协同作用现象需要更好地理解，因为它发生在病毒与宿主相遇期间，需要确定最有效的协同伙伴。在这个项目中，我们将设计新的有效的HIV-1细胞进入拮抗剂，包括我们合作的研究小组正在开发的抑制剂的共价融合。此外，我们将寻求识别活性提高的协同组合，评估协同作用的机制属性，确定在不同细胞环境中抗病毒协同的潜力，并评估协同组合避免病毒突变逃逸的能力。该项目将在中国科学院和德雷克塞尔大学的科学环境中促进HIV-1抑制剂设计和机理研究的研究。通过该项目支持的合作将因各自机构之间建立的翻译计划而得到进一步加强，而该项目反过来又将有助于推动机构之间的翻译合作。

DESCRIPTION (provided by applicant): This research project is a joint effort by laboratories at the Chinese Academy of Sciences in Shanghai and Drexel University in Philadelphia to pursue the development of new classes of HIV-1 inhibitors targeting cell entry and to investigate the underlying hypothesis that antagonists of HIV-1 Env and host cell co-receptors can be combined in synergistic combinations to improve antiviral activity and decrease the susceptibility to function-compromising viral resistance. New agents for HIV-1 intervention remain urgently needed to reduce the effects of the global occurrence and spread of AIDS. HIV-1 infection of host cells is initiated by the interaction of the Env protein complex on the exposed surface of the virus with two cell receptors, CD4 and a co-receptor that is most commonly CCR5 and CXCR4. In our collaborating laboratories, we have been investigating new peptide triazole gp120 antagonists that can inactivate the virus and both CCR5 and CXCR4 co-receptor antagonists. Prior studies and our own preliminary results suggest that coordinately acting inhibitors targeting Env and co-receptor can improve the potential use of these types of inhibitors in prevention and therapeutic intervention. The phenomenon of synergy for these entry inhibitors needs to be better understood as it occurs during virus-host encounter, and maximally active synergy partners need to be identified. In this project, we will design new and potent antagonists of HIV-1 cell entry, including covalent fusions of inhibitors being developed in our collaborating research groups. Furthermore, we will seek to identify improved-activity synergistic combinations, evaluate mechanistic properties underlying the synergy, define the potential for antiviral synergy in different cellular environments, and evaluate the ability of the synergistic combinations to avoid virus mutagenic escape. This project will foster research in the scientific environments of both the Chinese Academy of Sciences and Drexel University on HIV-1 inhibitor design and mechanism studies. The collaboration supported through this project will be further enhanced by a translational program being established between the respective institutions, and the project in turn will help drive translational collaborations between the institutions.