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Structure-guided design of protease-resistant, lipopeptide inhibitors of SARS-CoV-2

SARS-CoV-2 蛋白酶抗性脂肽抑制剂的结构指导设计

基本信息

批准号：
10679139
负责人：
Ariel Jade Kuhn
金额：
$ 6.87万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679139
关键词：
2019-nCoV Address Amino Acid Substitution Amino Acids Animal Model Antiviral Agents Biodistribution Biological Assay Biological Availability C-terminal COVID-19 COVID-19 therapeutics Cell membrane Cells Cessation of life Chemicals Cholesterol Circular Dichroism Collaborations Coronavirus Crystallization Crystallography Data Development Dose Drug Kinetics Economics Engineering Etiology Exhibits Fluorescence Polarization Foundations Goals HIV Half-Life Hybrids In Vitro Infection Learning Length Mediating Membrane Fusion Membrane Proteins Middle East Respiratory Syndrome Modification Molecular Molecular Conformation N-terminal Para-Influenza Virus Type 3 Pathogenesis Peptide Hydrolases Peptides Positioning Attribute Predisposition Productivity Property Prophylactic treatment Protein Engineering Proteins Proteolysis Research Research Personnel Resistance Resolution SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 variant Side Site Structure Surface Techniques Therapeutic Agents Treatment Efficacy Universities Vaccines Variant Vertebral column Viral Viral Physiology Virus Virus Diseases Virus Inhibitors Vulnerable Populations Wisconsin Work X ray diffraction analysis X-Ray Crystallography analog career coronavirus disease design experience improved in vivo inhibitor insight interdisciplinary approach mimicry novel novel strategies novel therapeutics pandemic disease protein expression viral entry inhibitor virology

项目摘要

PROJECT SUMMARY Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease (COVID-19), has spurred an unprecedented global pandemic. Infection surges necessitate new therapeutic agents that are effective against a rapidly changing virus. Antivirals that inhibit viral entry into host cells have proven effective against other viruses with similar mechanisms of pathogenesis. The long-term objective of this highly collaborative proposed research is to develop potent peptides inhibitors of SARS-CoV-2 infection that operate by blocking structural rearrangements of the spike protein required for viral entry into host cells. For SARS-CoV-2 infection to occur, the viral surface spike (S) protein, a homotrimer, rearranges to form an energetically favored postfusion state. In this postfusion conformation, two helical domains, the N-terminal (HRN) and C-terminal (HRC) heptad repeats, associate to form a 6-helix bundle (6HB). Peptides derived from the HRC can inhibit formation of the 6HB, and thus SARS-CoV-2 infection. However, conventional peptides, composed entirely of α-amino acid residues, are highly susceptible to proteolytic degradation, which necessitates frequent and high dosing. The Gellman lab, in collaboration with virologists Prof. Anne Moscona and Prof. Matteo Porotto at Columbia University, has demonstrated that site- selective incorporation of backbone modifications, in combination with cholesterol conjugation, can decrease proteolytic sensitivity while maintaining high antiviral potency. Our team recently found that such lipopeptides can inhibit SARS-CoV-2 infection in biological assays and animal models, and that these inhibitors are effective against SARS-CoV-2 variants, SARS-CoV-1 and MERS. Building on this foundation, my proposed project seeks to develop lipopeptides containing backbone modifications that display high antiviral potency and resist proteolysis. Aim 1 will produce potent inhibitors of SARS-CoV-2 (and other coronaviruses) that contain backbone modifications and resist proteolysis. Aim 2 will evaluate the stability of 6HB formation between inhibitor candidates and the native SARS-CoV-2 HRN. Aim 3 will elucidate critical structural interactions between the HRC mimics and the native HRN. My hypothesis is that site-selective incorporation of backbone modifications into HRC-based designs will increase both antiviral activity and half-life in vivo, improving therapeutic efficacy. The proposed research, which will be conducted under the guidance of Prof. Sam Gellman at the University of Wisconsin, will provide me with experience in macromolecular X-ray crystallography, molecular design, protein engineering & expression, and virology. Through structure-guided engineering and sophisticated and multi-pronged assay implementation, these efforts could generate effective pan-variant therapeutics for COVID-19.

项目总结