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

摘要 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， 这就需要快速开发安全有效的医疗对策。SARS-CoV-2致病性 需要一系列的蛋白质-蛋白质相互作用（PPI），涉及病毒的蛋白质，导致病毒附着 和融合。最初，S蛋白S1亚基上的受体结合结构域（RBD）结合到ACE 2受体上。 宿主细胞这引发了S蛋白S2亚基的构象变化，驱动病毒七肽重复序列1 (HR1)和S2的七肽重复2（HR 2）结构域形成六螺旋束（6-HB），使得病毒包膜 使其靠近宿主细胞膜，从而促进病毒融合。肽已经出现 最近作为能够以高亲和力和特异性靶向和破坏PPI的治疗类别。我们 假设肽治疗剂对病毒S蛋白的拮抗作用将提供有效的抗病毒药物 SARS-CoV-2感染的策略，以及潜在的泛冠状病毒干预。我们提出一个计划， 基于靶点结合和体外病毒中和的先导候选肽拮抗剂， 逃逸突变体，和减毒的病毒载量和脱落在雪貂攻击模型在体内。成功 该计划的完成将支持领先的候选肽推进IND使能研究， 提供提交II期SBIR提案的理由，以评估重度 呼吸道疾病

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.