Covalent inhibitors of host cell entry by SARS-CoV-2 for treatment of COVID-19

项目摘要 目前克服病毒暴发的战略重点是开发有效的疫苗以及 新的治疗方法，既可以阻止感染，也可以防止由此导致的疾病死亡。其中一个 已经显示出希望的策略是使用感染康复患者的血清。这 策略依赖于存在与病毒和病毒上的抗原结合的高滴度中和抗体 阻断宿主细胞的摄取。对于SARS-CoV-2病毒来说，这需要结合到 病毒‘尖峰’蛋白(S)的受体结合域并阻断其与宿主受体的相互作用， 血管紧张素转换酶2(ACE2)。过去15年来对相关研究的重大努力 冠状病毒已经绘制了这两个蛋白质结构域之间相互作用的详细图片。这些 研究促进了选择最佳中和抗体的策略，这些中和抗体可能具有最大的 治疗价值。虽然抗体是有效的生物疗法，但它们受到的限制使 它们的广泛使用对全球大流行的影响有限。这包括较高的生产成本、较差的购买力 口头或局部管理，与长期储存和储存普遍不相容。此外， 与靶病毒蛋白的相互作用是可逆的，可使抗体失效。 通过病毒变种的单点突变进行中和。在这项建议中，我们概述了制定一项 噬菌体展示筛选方法鉴定携带共价“弹头”诱导的合成环肽 与SARS-CoV-2 S蛋白高度保守和功能重要的特异性和永久性结合 残留物。这一方法将导致识别完全合成的分子，这些分子不可逆转地阻止密钥 S蛋白RBD与宿主细胞受体ACE2的相互作用这样的分子将拥有 抗体具有选择性，但可以像小分子药物一样合成和处理。此外，他们的 共价结合模式会导致治疗效果延长和诱导耐药性的能力降低 导致S蛋白发生突变。

Project Summary Current strategies to overcome virus outbreaks are focused on development of effective vaccines as well as novel treatments that can either block infection or prevent mortality from the resulting disease. One of the strategies that has shown promise is the use of serum from patients who have recovered from infection. This strategy relies on the presence of high titers of neutralizing antibodies that bind to antigens on the virus and block uptake into host cells. For the SARS-CoV-2 virus this requires antibodies that bind to regions on the receptor binding domain (RBD) of the viral ‘spike’ (S) protein and block its interaction with the host receptor, angiotensin converting enzyme 2 (ACE2). Significant efforts over the past 15 years of studies on related coronaviruses has produced a detailed picture of the interactions between these two protein domains. These studies have facilitated strategies to select optimal neutralizing antibodies likely to have the greatest therapeutic value. While antibodies are effective biological therapies, they suffer from limitations that make their widespread use for a global pandemic limited. This includes the high cost of production, poor uptake by oral or localized administration and general incompatibility with long-term storage and stockpiling. Furthermore, interactions with the target viral proteins are reversible and can be rendered ineffective for antibody neutralization through single point mutations in virus variants. In this proposal, we outline plans to develop a phage display screening approach to identify synthetic cyclic peptides that carry a covalent ‘warhead’ to induce specific and permanent binding to the SARS-CoV-2 S protein at highly conserved and functionally important residues. This approach will lead to the identification of fully synthetic molecules that irreversibly block key interactions between the S protein RBD and the host cell receptor, ACE2. Such molecules will possess the selectivity of antibodies but can be synthesized and handled like small molecule drugs. Furthermore, their covalent binding mode will lead to prolonged therapeutic effects and reduced ability to induce resistance causing mutations in the S protein.