Development of Novel Therapies for HIV Infection

HIV感染新疗法的开发

• 批准号: 7969764
• 负责人: Robert Yarchoan
• 金额: $ 57.36万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969764
• 关键词: Area; Cells; Cleaved cell; Clinical Trials; Collaborations; Cysteine; Development; Diagnosis; Dimerization; Disease; Engineering; Enzymes; Gagging; Goals; HIV; HIV-1; Immune response; Laboratories; Lamivudine; Life Cycle Stages; Pathogenesis; Patients; Peptide Hydrolases; Peptide Vaccines; Peptides; Pharmaceutical Preparations; Production; Protease Inhibitor; RNA-Directed DNA Polymerase; Research; Resistance; Resistance development; Therapeutic; Vaccines; Viral; Virus Diseases; Virus Replication; base; design; dimer; drug development; inhibitor/antagonist; monomer; mutant; novel; pol Gene Products; protein aminoacid sequence; response; small molecule; therapeutic vaccine

During the past year, the Retroviral Diseases Section has conducted research on human immunodeficiency virus (HIV) disease. We have been focusing on two areas: the HIV protease and developing an immune response to peptide sequences that confer resistance to anti-HIV drugs. The first part of the project is exploring the feasibility of developing a novel therapy to HIV protease through inhibition of HIV protease dimerization. HIV protease is a dimer composed of two identical monomers. Our group previously found that glutathiolation of a conserved cysteine (Cys 95) at the HIV protease dimer interface abolishes HIV-1 protease activity. This suggested that the dimer interface and inhibition of dimerization could be a novel target for drug development. We showed that several peptides could be designed that interfered with HIV protease dimerization and that this peptide could block HIV viral production from infected cells. We are exploring the effect of these inhibitors on the Gag-Pol polyprotein, which needs to form a dimer and self-cleave itself to form active protease. Our hypothesis is that such dimerization inhibitors may be optimally directed at this initial dimerization of the Gag-Pol polyproteins. We are also exploring a number of small molecule inhibitors of HIV protease for their activity against Gag-Pol and against dimerization, in part in collaboration with the laboratory of Dr. Mitsuya. We have found that the protease inhibitor darunavir also has activity in inhibiting HIV protease dimerization. We have also been exploring the possibility of designing a peptide vaccine to HIV that could induce an immune response to a viral sequence that confers resistance to an HIV drug. In collaboration with Dr. Jay Berzofsky, we have engineered such an peptide that can induce a response against the M184V sequence of HIV reverse transcriptase that confers resistance to lamivudine and emtracitabine, and have initiated a clinical trial to explore this as a therapeutic vaccine. In addition, we are conducting some studies on the diagnosis and pathogenesis of HIV infection.

去年，逆转录病毒疾病科开展了人类免疫缺陷病毒（HIV）疾病的研究。我们一直专注于两个领域：HIV 蛋白酶和开发针对赋予抗 HIV 药物耐药性的肽序列的免疫反应。 该项目的第一部分是探索通过抑制艾滋病毒蛋白酶二聚化开发艾滋病毒蛋白酶新疗法的可行性。 HIV蛋白酶是由两个相同单体组成的二聚体。我们的小组之前发现，HIV 蛋白酶二聚体界面上保守的半胱氨酸 (Cys 95) 的谷胱甘肽化会消除 HIV-1 蛋白酶活性。这表明二聚体界面和二聚化抑制可能成为药物开发的新靶点。我们表明，可以设计几种干扰 HIV 蛋白酶二聚化的肽，并且这种肽可以阻止受感染细胞产生 HIV 病毒。我们正在探索这些抑制剂对 Gag-Pol 多蛋白的影响，该多蛋白需要形成二聚体并自我裂解以形成活性蛋白酶。我们的假设是，此类二聚化抑制剂可能最佳地针对 Gag-Pol 多蛋白的初始二聚化。我们还在与 Mitsuya 博士的实验室合作，探索一些 HIV 蛋白酶小分子抑制剂的抗 Gag-Pol 和二聚化活性。我们发现蛋白酶抑制剂达芦那韦也具有抑制HIV蛋白酶二聚化的活性。我们还一直在探索设计一种艾滋病毒肽疫苗的可能性，这种疫苗可以诱导对病毒序列的免疫反应，从而对艾滋病毒药物产生耐药性。我们与 Jay Berzofsky 博士合作，设计了这样一种肽，它可以诱导针对 HIV 逆转录酶 M184V 序列的反应，从而产生对拉米夫定和恩曲他滨的耐药性，并启动了一项临床试验，探索将其作为治疗性疫苗。另外，我们正在开展一些关于HIV感染的诊断和发病机制的研究。