STTR Phase I: Discovery and Development of Macrocyclic Peptide Inhibitors of SARS-COV-2 Spike Protein for the Treatment of COVID-19

小企业技术转让（STTR）第一阶段项目的更广泛影响/商业潜力在于发现和开发一流的治疗方法，作为COVID-19病毒感染的抗病毒治疗。 在拟议的研究中，将确定基于环肽的新型有效的抗病毒候选药物。与基于小分子的药物相比，肽将在靶向蛋白质-蛋白质相互作用方面提供优势。同时，肽及其代谢产物由于其作为生物构件的性质，具有更有利的安全性特征。此外，肽类药物在发现、开发和制造方面具有时间和成本效益，这使得它们比抗体和其他生物制剂更具吸引力。基于肽的药物发现平台可以潜在地应用于许多未满足的医疗需求的治疗靶点。通过拟议的研究获得的知识和经验将很容易应用于其他适应症和潜在的未来大流行病。这个小企业技术转让（STTR）第一阶段项目将确定小环肽作为治疗COVID-19病毒感染的新型候选药物。破坏SARS-COV-2刺突蛋白及其同源细胞受体ACE 2相互作用的单克隆抗体在降低COVID-19患者的病毒负荷和缩短恢复时间方面显示出有希望的疗效。不幸的是，一系列挑战阻碍了它们的潜在效用，包括高制造和运输成本。按照抗体的实例，小环肽能够破坏蛋白质-蛋白质相互作用。与抗体不同，小肽可以通过化学合成以时间和成本效益高的方式大规模生产，并以更适合患者的途径给药，如皮下和肌内注射。在拟议的项目中，专有的分子进化技术将被应用于有效筛选一个非常大的肽库（在4-8周内多达1010个肽）。将验证命中肽在破坏刺突蛋白与其宿主细胞受体ACE 2之间的相互作用以及随后抑制病毒进入ACE 2表达细胞中的效力。一旦完成了建议的研究，选定的候选人将被转移到第二阶段计划的优化和临床前的发展。这个奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的知识价值和更广泛的影响审查标准。

The broader impact /commercial potential of this Small Business Technology Transfer (STTR) Phase I project lies in the discovery and development of first-in-class therapeutics as an anti-viral treatment of COVID-19 viral infection. Within the proposed studies, cyclic peptide-based novel, effective anti-viral drug candidates will be identified. Compared to small molecule-based drugs, peptides will offer advantages in targeting protein-protein interactions. At the same time, peptides and their metabolites, due to their nature as biological building blocks, have more favorable safety profiles. Furthermore, peptide drugs are time- and cost-effective to discover, develop, and manufacture, which makes them more attractive than antibodies and other biologics. The peptide-based drug discovery platform can potentially be applied toward many therapeutic targets for unmet medical needs. The knowledge and experience gained through proposed studies will be readily applied to other indications and potentially future pandemics. This Small Business Technology Transfer (STTR) Phase I project will identify small cyclic peptides as novel drug candidates for the treatment of COVID-19 viral infection. Monoclonal antibodies that disrupt the interaction of SARS-COV-2 Spike protein and its cognate cellular receptor ACE2 have shown promising efficacy in reducing viral burden and shortening recovery time in COVID-19 patients. Unfortunately, a series of challenges hinder their potential utility including high cost of manufacturing and transportation. Small cyclic peptides are capable of disrupting protein-protein interactions following the examples of the antibodies. Unlike antibodies, small peptides can be manufactured in large scales in a time- and cost-effective manner through chemical synthesis and are administered in more patient-friendly routes such as subcutaneous and intramuscular injections. In the proposed project, a proprietary molecular evolution technology will be applied to efficiently screen an extremely large library of peptides(up to 1010 peptides within 4-8 weeks). Hit peptides will be validated for their potency in disrupting the interaction between Spike protein and its host cell receptor, ACE2, and subsequent inhibition of viral entry into ACE2 expressing cells. Upon the completion of proposed studies, selected candidates will be moved into a phase II program for optimization and preclinical development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.