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Inhibition of SARS-CoV-2 infection with a pan-coronavirus anti-viral peptide

泛冠状病毒抗病毒肽抑制 SARS-CoV-2 感染

基本信息

批准号：
10256216
负责人：
Jim Rotolo
金额：
$ 29.99万
依托单位：
SAPIENCE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-04 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256216
关键词：
2019-nCoV ACE2 Affinity Antibodies Antiviral Agents Antiviral Therapy Automobile Driving Binding Biochemical Biological Availability COVID-19 pandemic COVID-19 therapeutics COVID-19 treatment Cells Complex Coronavirus Coronavirus Infections Data Development Dose Electrostatics Engineering Ensure Enzyme-Linked Immunosorbent Assay Escape Mutant Evaluation Ferrets Future Generations Genes Genome HIV-1 Human In Vitro Infection Inhalation Intervention Invaded Lead Length Lung diseases Measures Membrane Methods Modeling Molecular Conformation Molecular Sieve Chromatography Mutation Organelles Pathogenicity Peptides Phase Proteins Public Health Quantitative Reverse Transcriptase PCR RNA Resistance Risk SARS-CoV-2 infection SARS-CoV-2 spike protein Series Small Business Innovation Research Grant Specificity Surface Plasmon Resonance Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Validation Vero Cells Viral Viral Load result Viral Proteins Viral load measurement Virus Virus Diseases Virus Shedding Zoonoses attenuation base betacoronavirus coronavirus antiviral coronavirus disease design drug candidate experimental study human disease in vitro activity in vivo in vivo Model in vivo evaluation inhibitor/antagonist lead candidate manufacturing process medical countermeasure novel novel therapeutics peptide drug pressure prevent programs protein aminoacid sequence protein protein interaction receptor receptor binding response scale up targeted treatment therapeutic development therapy resistant viral transmission

项目摘要

ABSTRACT The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is a serious threat to global public health, necessitating the rapid development of safe and effective medical countermeasures. SARS-CoV-2 pathogenicity requires a series of protein-protein interactions (PPI) involving the virus’ S protein that leads to virus attachment and fusion. Initially, the receptor binding domain (RBD) on the S protein S1 subunit binds to ACE2 receptors on the host cell. This triggers a conformational change in the S protein S2 subunit, driving the viral heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains of S2 to form a six-helical bundle (6-HB), enabling the viral envelope to be brought in close proximity to the host membrane, thus promoting viral fusion. Peptides have emerged recently as a therapeutic class capable of targeting and disrupting PPI with high affinity and specificity. We hypothesize antagonism of the virus S protein with a peptide therapeutic will provide an effective anti-viral strategy for SARS-CoV-2 infection, and potentially a pan-coronavirus intervention. We propose a plan to select a lead candidate peptide antagonist based upon target binding and viral neutralization in vitro, with consideration of escape mutants, and attenuation of virus load and shedding in a ferret challenge model in vivo. Successful completion of this program will support advancement of the lead candidate peptide to IND-enabling studies, and provide the rationale for submission of a Phase II SBIR proposal to evaluate inhalation delivery for severe respiratory disease.

摘要由SARS-CoV-2病毒引起的新冠肺炎疫情对全球公共卫生构成严重威胁，因此有必要迅速制定安全有效的医学对策。SARS-CoV-2的致病性需要一系列的蛋白质-蛋白质相互作用(PPI)，涉及病毒的S蛋白，导致病毒附着和核聚变。最初，S蛋白S1亚基上的受体结合域与血管紧张素转换酶2受体结合。宿主细胞。这触发了S蛋白S2亚基的构象变化，驱动病毒七肽重复序列1 S2的(HR1)和七肽重复序列2(HR2)结构域形成一个六螺旋束(6-HB)，使病毒包膜成为可能被带到靠近宿主膜的地方，从而促进病毒融合。多肽已经出现最近被认为是一种具有高亲和力和特异性的靶向和干扰PPI的治疗类别。我们假想拮抗病毒S蛋白的多肽治疗将提供一种有效的抗病毒 SARS-CoV-2感染的战略，以及潜在的泛冠状病毒干预。我们提出一项计划，选择一种基于靶向结合和体外病毒中和的主要候选多肽拮抗剂在体内的雪貂攻击模型中，逃逸突变体的数量，以及病毒负载和脱落的减弱。成功这项计划的完成将支持将主要候选肽推进到IND使能研究，以及提供提交第二阶段SBIR建议的理由，以评估重症患者的吸入给药呼吸道疾病。