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

这项小型企业技术转让（STTR）第一阶段项目的更广泛影响/商业潜力在于发现和开发作为COVID-19病毒感染抗病毒治疗的一流疗法。在拟议的研究中，基于环肽的新型有效抗病毒候选药物将被确定。与基于小分子的药物相比，多肽在靶向蛋白质-蛋白质相互作用方面具有优势。与此同时，多肽及其代谢产物，由于其作为生物组成部分的性质，具有更有利的安全性。此外，多肽药物的发现、开发和生产既省时又划算，这使得它们比抗体和其他生物制剂更有吸引力。基于肽的药物发现平台可以潜在地应用于许多治疗靶点，以满足未满足的医疗需求。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未来可能出现的大流行病。该小型企业技术转移（STTR）一期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ACE2相互作用的单克隆抗体在减轻COVID-19患者的病毒负担和缩短恢复时间方面显示出良好的疗效。不幸的是，一系列的挑战阻碍了它们的潜在效用，包括高成本的制造和运输。小环肽能够破坏蛋白质之间的相互作用，如抗体的例子所示。与抗体不同，小肽可以通过化学合成以时间和成本效益的方式大规模生产，并以更有利于患者的途径（如皮下和肌肉注射）给药。在拟议的项目中，专利分子进化技术将应用于有效筛选一个巨大的肽库（在4-8周内多达1010个肽）。Hit肽在破坏Spike蛋白与其宿主细胞受体ACE2之间的相互作用以及随后抑制病毒进入表达ACE2的细胞方面的效力将得到验证。在完成拟议的研究后，选定的候选药物将进入II期项目进行优化和临床前开发。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.