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：
10401492
负责人：
Jim Rotolo
金额：
$ 28.82万
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/10401492
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 Measures Membrane Methods Modeling Molecular Conformation Molecular Sieve Chromatography Mutation Organelles Pathogenicity Peptides Phase Proteins Public Health Quantitative Reverse Transcriptase PCR RNA Resistance Respiratory Disease 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 antagonist 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 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.

抽象的由 SARS-CoV-2 病毒引起的 COVID-19 大流行对全球公共卫生构成严重威胁，需要快速开发安全有效的医疗对策来应对 SARS-CoV-2 的致病性。需要一系列涉及病毒 S 蛋白的蛋白质-蛋白质相互作用 (PPI)，从而导致病毒附着最初，S 蛋白 S1 亚基上的受体结合域 (RBD) 与 ACE2 受体结合。这会触发 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 2 (HR2) 结构域形成六螺旋束 (6-HB)，从而使病毒包膜被带到靠近宿主膜，从而促进病毒融合的肽已经出现。最近作为一种能够以高亲和力和特异性靶向和破坏 PPI 的治疗类别。用肽治疗剂开发对病毒 S 蛋白的拮抗作用将提供有效的抗病毒药物我们提出了一项针对 SARS-CoV-2 感染的策略，以及可能的泛冠状病毒干预措施。基于体外靶标结合和病毒中和的主要候选肽拮抗剂，考虑到逃逸突变体的数量，以及雪貂体内攻击模型中病毒载量的减弱和脱落。该计划的完成将支持将主要候选肽推进 IND 研究，并且提供提交第二阶段 SBIR 提案的理由，以评估重症患者的吸入给药呼吸道疾病。