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

针对 HIV-1 Env 和宿主细胞共受体的抑制剂的抗病毒协同作用

• 批准号: 8721338
• 负责人: IRWIN M CHAIKEN
• 金额: $ 20万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721338
• 关键词: Academy; Acquired Immunodeficiency Syndrome; Agreement; Antiviral Agents; Binding; Binding Sites; CCR5 gene; CD4 Antigens; CXCR4 gene; Cell membrane; Cells; Characteristics; Chemokine (C-C Motif) Receptor 5; Chimera organism; Chinese People; Collaborations; Development; Environment; Exposure to; Fostering; Future; HIV Envelope Protein gp120; HIV-1; In Vitro; Individual; Infection; Infection prevention; Institution; Intervention; Investigation; Joints; Laboratories; Mutation; New Agents; Pattern; Peptides; Philadelphia; Predisposition; Preventive Intervention; Property; Receptor Cell; Research; Research Personnel; Research Project Grants; Science; Staging; Surface; Synapses; System; Therapeutic Intervention; Toxic effect; Triazoles; Tropism; Universities; Virus; Virus Diseases; Work; design; env Gene Products; improved; inhibitor/antagonist; microbicide; next generation; novel; programs; protein complex; public health relevance; receptor; receptor binding; synergism; transmission process; viral resistance

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.

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功能强化病毒抗性。 HIV-1干预的新药物仍然需要迫切需要减少艾滋病的全球发生和传播的影响。宿主细胞的HIV-1感染是由Env蛋白复合物在暴露表面上的相互作用引发的 带有两个细胞受体CD4和最常见的CCR5和CXCR4的共受体的病毒。在我们的合作实验室中，我们一直在研究新的肽三唑GP120拮抗剂，这些拮抗剂可能使病毒失活以及CCR5和CXCR4共受体拮抗剂。先前的研究和我们自己的初步结果表明，靶向靶向的抑制剂 ENV和共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使用。这些进入抑制剂的协同作用现象需要更好地理解，因为它在病毒宿主相遇过程中发生，并且需要确定最大活跃的协同伴侣。在这个项目中，我们将设计HIV-1细胞进入的新的和有力的拮抗剂，包括在我们的协作研究小组中开发的抑制剂的共价融合。此外，我们将寻求确定改善的活动协同组合，评估协同作用的机械性能，确定在不同细胞环境中抗病毒协同作用的潜力，并评估协同组合以避免病毒诱变逃逸的能力。该项目将在中国科学院的科学环境和Drexel大学的HIV-1抑制剂设计和机理研究中促进研究。通过该项目支持的合作将通过各自机构之间建立的翻译计划进一步增强，而该项目又将有助于推动机构之间的转化合作。