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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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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:
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