CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies

抗体是由免疫系统产生的。它们能识别外来的感染源。它们的分子识别能力使它们成为感知和治疗疾病的理想选择。然而，它们在结合和阻断蛋白酶的作用方面没有用处。这一点很重要，因为蛋白酶活性可以触发癌症的发展。例如，参与癌症发展的关键蛋白酶，称为基质金属蛋白酶(MMPs)，在癌症发展和糖尿病期间过度产生。本项目的目的是评价用独特的氨基酸修饰抗体对基质金属蛋白酶活性调节的影响。该提案的教育部分旨在加强塔夫茨STEM大使计划，并加强与地区职业/技工高中生物技术计划的合作伙伴关系。胞外蛋白酶和肽酶在人类健康和疾病中发挥关键作用。这些酶的具体破坏仍然是一个根本性的挑战。例如，基质金属蛋白酶(MMPs)在发育、炎症、癌症和传染病中发挥关键作用。高度特异性的抑制剂对于揭示酶的分子功能和建立具有改进治疗潜力的新一代抑制剂是必不可少的。总的目标是建立“化学多样化”抗体的原理，使下一代蛋白酶抑制剂的发现成为可能。该项目将评估非规范氨基酸和酵母展示技术的集成，以开发抗体中的共价(不可逆)结合和金属结合功能。研究人员希望发现能够干扰酶功能的化学物质。这些研究还可以确定将化学物质添加到抗体中会导致具有常规抗体无法设计的属性(如效力、作用时间或特定表位靶向)的抑制剂的使用案例。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Antibodies are created by the immune system. They recognize foreign infectious agents. Their molecular recognition capabilities make them ideal to sense and to treat diseases. They are, however, not useful in binding to and blocking the action of proteases. This is important because protease activity can trigger the development of cancers. Key proteases involved in cancer development, called matrix metalloproteases (MMPs), are overproduced during the development of cancer and during diabetes, for example. The objective of this project is to evaluate the impact of modifying antibodies with unique amino acids on the regulation of MMP activity. The education component of this proposal seeks to enhance the Tufts STEM Ambassadors program and strengthen a partnership with the biotechnology program of an area vocational/technical high school.Extracellular proteases and peptidases play key roles in human health and disease. The specific disruption of these enzymes remains a fundamental challenge. For example, matrix metalloproteinases (MMPs) play key roles in development, inflammation, cancer, and infectious disease. Highly specific inhibitors are essential for uncovering the molecular functions of enzymes and for establishing a new generation of inhibitors with improved therapeutic potential. The overall goal is to establish principles of “chemically diversified” antibodies that enable next-generation protease inhibitor discovery. This project will evaluate integration of noncanonical amino acids and yeast display technology to exploit covalent (irreversible) binding and metal binding functionalities within antibodies. The investigators hope to discover chemistries capable of interfering with enzyme functions. These studies could also identify use cases where adding chemistries to antibodies leads to inhibitors with properties (such as potency, duration of action, or specific epitope targeting) that cannot be engineered into conventional antibodies.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.