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Targeting SARS-Related Coronaviruses with a D-peptide Entry Inhibitor

Targeting SARS-Related Coronaviruses with a D-peptide Entry Inhibitor
使用 D 肽进入抑制剂靶向 SARS 相关冠状病毒
批准号:
10189371
负责人:
Michael S Kay
金额:
$42.95万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-15 至 2023-08-31

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项目成果

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中文摘要
翻译
项目摘要 21世纪出现了多种致死性人类冠状病毒(SARS冠状病毒、MERS冠状病毒、 现在是SARS-CoV-2)。迫切需要有治疗选择来对抗当前和不可避免的 未来类似SARS的大流行。冠状病毒通过与病毒相同的保守进入机制感染细胞 跨越多个家庭(包括艾滋病毒、埃博拉和流感),其中两个区域的三聚体病毒激增 蛋白质(HR1和HR2)崩溃形成高度稳定的六螺旋束结构,迫使病毒和 细胞膜聚集在一起,诱导膜融合。与HR1结合的抑制剂阻断六股螺旋束 形成并阻止病毒进入,防止感染。我们的实验室专门研究镜像噬菌体展示(MIPD), 一种创新的方法来鉴定新的合成抗蛋白酶D肽候选药物,具有特殊的 重点是抑制病毒进入(我们的HIV-1药物CPT31将开始临床试验)。D-肽 (由镜像D-氨基酸组成的多肽)不能被体内的蛋白酶消化, 因此,具有显著的治疗优势,包括延长半衰期,降低剂量,减少 免疫原性(不为MHC呈现而消化),以及在富含蛋白酶的环境中的持久性,例如 呼吸道。为了解决目前的健康危机,我们正在加快我们的药物发现进程,以确定 靶向SARS相关冠状病毒保守的HR1的D-肽进入抑制剂。我们设计了, 合成并表征了我们的HR1模拟药物靶点,并将其用于MIPD中的D-肽的鉴定 6-螺旋束形成和病毒进入的抑制剂。 在这项计划中,我们将化学合成MIPD识别的D-肽,并对其进行表征 抗SARS-CoV和SARS-CoV-2的靶向亲和力(表面等离子体共振)和抗病毒活性 伪病毒。有希望的D-肽将使用第二轮MIPD来优化亲和成熟 威力。使用我们定制设计的聚乙二醇支架(CPT31的主干),我们将把最高的 亲和D-肽候选以提高对三聚体刺激靶的亲和力并附着膜定位 例如胆固醇,它将丰富病毒进入细胞部位的D-肽,并在体内改善 半衰期。这些领先的D-肽将针对真正的病毒进行测试(与USU的研究所合作 用于抗病毒研究)。我们的目标是在体外获得一种与≤100nM结合的D-肽候选细胞株 SARS-CoV-2和SARS良好的治疗指数(EC50/CC50>100)进展为体内PK和疗效 研究方面,采用USU的仓鼠SARS-CoV-2感染模型。在授权期结束时,我们预计 有一种具有体内动物功效的D-肽先导,准备用于IND的临床前研究 以及作为SARS相关冠状病毒治疗和/或预防的发展。
英文摘要
Project Summary The 21st century has seen the emergence of multiple lethal human coronaviruses (SARS-CoV, MERS-CoV, and now SARS-CoV-2). There is an urgent need for therapeutic options to combat the current and inevitable future SARS-like pandemics. Coronaviruses infect cells using a conserved entry mechanism shared by viruses across multiple families (including HIV, Ebola, and influenza) in which two regions of the trimeric viral spike protein (HR1 and HR2) collapse to form a highly stable six-helix bundle structure that forces the viral and cellular membranes together, inducing membrane fusion. Inhibitor binding to HR1 blocks six-helix bundle formation and stops viral entry, preventing infection. Our lab specializes in mirror-image phage display (MIPD), an innovative approach to identify novel synthetic protease-resistant D-peptide drug candidates, with a special focus on the inhibition of viral entry (with our HIV-1 drug, CPT31, set to begin clinical trials). D-peptides (peptides composed of mirror-image D-amino acids) cannot be digested by proteases in the body and, therefore, possess significant therapeutic advantages including extended half-life, lower dosing, reduced immunogenicity (not digested for MHC presentation), and durability in protease-rich environments such as the respiratory tract. To address the current health crisis, we are expediting our drug discovery process to identify D-peptide entry inhibitors that target the conserved HR1 of SARS-related coronaviruses. We have designed, synthesized, and characterized our HR1 mimic drug targets and are using them in MIPD to identify D-peptide inhibitors of 6-helix bundle formation and viral entry. In this proposal, we will chemically synthesize the D-peptides identified by MIPD and characterize their target affinity (using surface plasmon resonance) and antiviral activity against SARS-CoV and SARS-CoV-2 pseudoviruses. Promising D-peptides will be affinity-matured using a second round of MIPD to optimize potency. Using our custom-designed PEG scaffold (the backbone of CPT31), we will trimerize the highest affinity D-peptide candidates to improve avidity for the trimeric spike target and attach a membrane-localizing group, such as cholesterol, that will enrich the D-peptide at the cellular site of viral entry and improve in vivo half-life. These leading D-peptides will be tested against authentic virus (in collaboration with USU's Institute for Antiviral Research). Our objective is to have one D-peptide candidate with ≤100 nM in vitro EC90 against SARS-CoV-2 and SARS and a good therapeutic index (EC50/CC50 >100) to advance to in vivo PK and efficacy studies, using USU's hamster model of SARS-CoV-2 infection. At the end of the grant period, we expect to have one D-peptide lead with demonstrated in vivo animal efficacy, poised for IND-enabling preclinical studies and development as a SARS-related coronavirus treatment and/or preventative.
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University of Utah Medical Scientist Training Program
  • 批准号:
    10628815
  • 项目类别:
  • 资助金额:
    $34.83万
  • 财政年份:
    2023
  • 负责人:
    Michael S Kay
  • 依托单位:
CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics
  • 批准号:
    10508314
  • 项目类别:
  • 资助金额:
    $30.33万
  • 财政年份:
    2022
  • 负责人:
    Michael S Kay
  • 依托单位:
CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics
  • 批准号:
    10663353
  • 项目类别:
  • 资助金额:
    $28.21万
  • 财政年份:
    2022
  • 负责人:
    Michael S Kay
  • 依托单位:
design and rapid production of a drug-screening target from the highly conserved HR1 region of the viral spike protein (S2)
  • 批准号:
    10221150
  • 项目类别:
  • 资助金额:
    $44.94万
  • 财政年份:
    2020
  • 负责人:
    Michael S Kay
  • 依托单位:
海外基金